VCV000129239.26 - ClinVar

NM_175914.5(HNF4A):c.50-5C>T

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_175914.5(HNF4A):c.50-5C>T

Variation ID: 129239 Accession: VCV000129239.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44406053 (GRCh38) [ NCBI UCSC ] 20: 43034693 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 6, 2014	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_175914.5:c.50-5C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000457.6:c.116-5C>T		intron variant
NM_001030003.3:c.50-5C>T		intron variant
NM_001030004.3:c.50-5C>T		intron variant
NM_001258355.2:c.95-5C>T		intron variant
NM_001287182.2:c.41-5C>T		intron variant
NM_001287183.2:c.41-5C>T		intron variant
NM_001287184.2:c.41-5C>T		intron variant
NM_178849.3:c.116-5C>T		intron variant
NM_178850.3:c.116-5C>T		intron variant
NC_000020.11:g.44406053C>T
NC_000020.10:g.43034693C>T
NG_009818.1:g.55253C>T
LRG_483:g.55253C>T
LRG_483t1:c.50-5C>T
LRG_483t2:c.116-5C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000020.11:44406052:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.16873 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.16740

1000 Genomes Project 0.16873

Trans-Omics for Precision Medicine (TOPMed) 0.17668

The Genome Aggregation Database (gnomAD) 0.17964

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.19045

The Genome Aggregation Database (gnomAD), exomes 0.19746

Exome Aggregation Consortium (ExAC) 0.20079

Links

ClinGen: CA153113 dbSNP: rs745975 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HNF4A		-	-	GRCh38 GRCh37	611	624

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Apr 24, 2019	RCV000117237.18
Hyperinsulinism, Dominant	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000268875.6
Maturity onset diabetes mellitus in young	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jun 14, 2016	RCV000361090.8
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000710147.13
Glycosuria	Benign (1)	criteria provided, single submitter	-	RCV002226672.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (May 08, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Maturity onset diabetes mellitus in young Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002643574.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 16946562 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000316595.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Maturity Onset Diabetes of the Young Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000433882.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Hyperinsulinism, Dominant Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000433883.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 10983627
Benign (Jul 12, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613648.2 First in ClinVar: Oct 02, 2016 Last updated: Oct 19, 2018	Publications: PubMed (8) PubMed: 15793260‚ 16883527‚ 16946562‚ 17573900‚ 18811724‚ 9267996‚ 9313765‚ 9449683
Benign (Apr 24, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001365799.1 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: The c.95-5C>T variant in HNF4A is classified as benign because it has been identified in 19.56% (55114/281792) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org/). Additionally, this … (more) The c.95-5C>T variant in HNF4A is classified as benign because it has been identified in 19.56% (55114/281792) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org/). Additionally, this variant does not alter the splice consensus sequence and is not predicted to impact splicing. ACMG/AMP criteria applied: BA1, BP4. (less) Number of individuals with the variant: 1
Benign (-)	criteria provided, single submitter (K&H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria) Method: research	Glycosuria Affected status: yes Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002505503.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (2) PubMed: 27846149‚ 19406499 Comment: Mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but … (more) Mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. As rs745975 SNP of HNF4α gene is associated with whole body insulin sensitivity and glucose tolerance and these factors are modulated by physical activity. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001725049.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005208725.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001864384.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 10983627, 25266181)
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000151410.2 First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
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Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The c.95-5C>T variant in HNF4A is classified as benign because it has been identified in 19.56% (55114/281792) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org/). Additionally, this variant does not alter the splice consensus sequence and is not predicted to impact splicing. ACMG/AMP criteria applied: BA1, BP4.

Comment:

Mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. These are associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. As rs745975 SNP of HNF4α gene is associated with whole body insulin sensitivity and glucose tolerance and these factors are modulated by physical activity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pyruvate Dehydrogenase Phosphatase Regulatory Gene Expression Correlates with Exercise Training Insulin Sensitivity Changes.	Barberio MD	Medicine and science in sports and exercise	2016	PMID: 27846149
Interaction between HNF4A polymorphisms and physical activity in relation to type 2 diabetes-related traits: results from the Quebec Family Study.	Ruchat SM	Diabetes research and clinical practice	2009	PMID: 19406499
Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus.	Plengvidhya N	Clinical endocrinology	2009	PMID: 18811724
Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain.	Estalella I	Clinical endocrinology	2007	PMID: 17573900
Novel genetic variations and haplotypes of hepatocyte nuclear factor 4alpha (HNF4A) found in Japanese type II diabetic patients.	Fukushima-Uesaka H	Drug metabolism and pharmacokinetics	2006	PMID: 16946562
[Scanning the HNF4A gene mutation from Chinese pedigrees with early- and/or multiple-onset diabetes].	Zhang R	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2006	PMID: 16883527
Genetic analysis of HNF4A polymorphisms in Caucasian-American type 2 diabetes.	Bagwell AM	Diabetes	2005	PMID: 15793260
Mutations in the hepatocyte nuclear factor-4alpha gene in Japanese with non-insulin-dependent diabetes: a nucleotide substitution in the polypyrimidine tract of intron 1b.	Sakurai K	Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme	2000	PMID: 10983627
A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.	Hani EH	The Journal of clinical investigation	1998	PMID: 9449683
Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY.	Furuta H	Diabetes	1997	PMID: 9313765
Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM.	Møller AM	Diabetologia	1997	PMID: 9267996
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Text-mined citations for rs745975 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_175914.5(HNF4A):c.50-5C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs745975 ...