VCV000137885.23 - ClinVar

NM_130839.5(UBE3A):c.1404A>G (p.Thr468=)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

3 conditions

Reviewed by expert panel

Benign

Mar 2021 by ClinGen Rett a… FDA Recognized Database

for Angelman syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_130839.5(UBE3A):c.1404A>G (p.Thr468=)

Variation ID: 137885 Accession: VCV000137885.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q11.2 15: 25370770 (GRCh38) [ NCBI UCSC ] 15: 25615917 (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	Oct 4, 2014	May 1, 2024	Mar 26, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_130839.5:c.1404A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_570854.1:p.Thr468=	synonymous
NM_000462.5:c.1413A>G	NP_000453.2:p.Thr471=	synonymous
NM_001354505.1:c.1404A>G	NP_001341434.1:p.Thr468=	synonymous
NM_001354506.2:c.1344A>G	NP_001341435.1:p.Thr448=	synonymous
NM_001354507.2:c.1344A>G	NP_001341436.1:p.Thr448=	synonymous
NM_001354508.2:c.1344A>G	NP_001341437.1:p.Thr448=	synonymous
NM_001354509.2:c.1344A>G	NP_001341438.1:p.Thr448=	synonymous
NM_001354511.2:c.1344A>G	NP_001341440.1:p.Thr448=	synonymous
NM_001354512.2:c.1344A>G	NP_001341441.1:p.Thr448=	synonymous
NM_001354513.2:c.1344A>G	NP_001341442.1:p.Thr448=	synonymous
NM_001354523.2:c.1344A>G	NP_001341452.1:p.Thr448=	synonymous
NM_001354526.1:c.1344A>G	NP_001341455.1:p.Thr448=	synonymous
NM_001354538.2:c.1404A>G	NP_001341467.1:p.Thr468=	synonymous
NM_001354539.2:c.1344A>G	NP_001341468.1:p.Thr448=	synonymous
NM_001354540.2:c.1344A>G	NP_001341469.1:p.Thr448=	synonymous
NM_001354541.2:c.1344A>G	NP_001341470.1:p.Thr448=	synonymous
NM_001354542.2:c.1344A>G	NP_001341471.1:p.Thr448=	synonymous
NM_001354543.2:c.1344A>G	NP_001341472.1:p.Thr448=	synonymous
NM_001354544.2:c.1344A>G	NP_001341473.1:p.Thr448=	synonymous
NM_001354545.2:c.1404A>G	NP_001341474.1:p.Thr468=	synonymous
NM_001354546.2:c.1227A>G	NP_001341475.1:p.Thr409=	synonymous
NM_001354547.2:c.1344A>G	NP_001341476.1:p.Thr448=	synonymous
NM_001354548.2:c.1344A>G	NP_001341477.1:p.Thr448=	synonymous
NM_001354549.2:c.1344A>G	NP_001341478.1:p.Thr448=	synonymous
NM_001354550.2:c.361+4695A>G		intron variant
NM_001354551.2:c.301+4695A>G		intron variant
NM_001374461.1:c.1344A>G	NP_001361390.1:p.Thr448=	synonymous
NM_130838.4:c.1344A>G	NP_570853.1:p.Thr448=	synonymous
NR_148916.2:n.1920A>G		non-coding transcript variant
NC_000015.10:g.25370770T>C
NC_000015.9:g.25615917T>C
NG_009268.1:g.73212A>G
LRG_15:g.73212A>G
LRG_15t1:c.1344A>G

... more HGVS ... less HGVS

Protein change

Other names

p.T468T:ACA>ACG

Canonical SPDI

NC_000015.10:25370769:T:C

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.

0.00559 (C)

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

The Genome Aggregation Database (gnomAD) 0.00054

Trans-Omics for Precision Medicine (TOPMed) 0.00060

Exome Aggregation Consortium (ExAC) 0.00112

The Genome Aggregation Database (gnomAD), exomes 0.00141

1000 Genomes Project 30x 0.00484

1000 Genomes Project 0.00559

Links

ClinGen: CA202443 dbSNP: rs150331504 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.
UBE3A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	40	1234
SNHG14		-	-	GRCh38	4	1133

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.
Angelman syndrome	Benign (3)	reviewed by expert panel	Mar 26, 2021	RCV000144353.30
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Jun 14, 2016	RCV000177396.19
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Nov 9, 2016	RCV002312891.9

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 (Mar 26, 2021)	reviewed by expert panel (ClinGen RettAS ACMG Specifications V1) Method: curation	Angelman syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel FDA Recognized Database Accession: SCV001711967.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/51ae3d53-3eb4-4e33-8f42-c4e08e83eb1f Comment: The allele frequency of the p.Thr448= variant in UBE3A is 1.9% in the East Asian sub population in gnomAD, which is high enough to be … (more) The allele frequency of the p.Thr448= variant in UBE3A is 1.9% in the East Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Thr448= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Thr448= variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP7). (less)
Benign (Aug 10, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000195340.2 First in ClinVar: Nov 23, 2014 Last updated: Oct 05, 2015
Benign (Jun 14, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169713.13 First in ClinVar: Jun 23, 2014 Last updated: Dec 06, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 07, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000229248.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=UBE3A http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=15&from=25615917&to=25615917 Number of individuals with the variant: 1 Sex: mixed
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Angelman syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291315.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (Nov 09, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000848955.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	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)
Uncertain significance (Feb 14, 2014)	no assertion criteria provided Method: clinical testing	Angelman syndrome Affected status: yes Allele origin: paternal	Baylor Genetics Study: UBE3A Mutation Study Accession: SCV000188530.1 First in ClinVar: Oct 04, 2014 Last updated: Oct 04, 2014 Comments (2): MAF 0.002 Data collected from clinical UBE3A sequence analysis results	Publications: PubMed (1) PubMed: 25212744 Comment: possible diagnosis of Angelman syndrome Number of individuals with the variant: 2

Comment:

The allele frequency of the p.Thr448= variant in UBE3A is 1.9% in the East Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Thr448= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Thr448= variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP7).

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=UBE3A	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/51ae3d53-3eb4-4e33-8f42-c4e08e83eb1f	-	-	-	-

Text-mined citations for rs150331504 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_130839.5(UBE3A):c.1404A>G (p.Thr468=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150331504 ...