VCV000370466.11 - ClinVar

NM_000135.4(FANCA):c.3761_3762del (p.Glu1254fs)

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.

(6)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000135.4(FANCA):c.3761_3762del (p.Glu1254fs)

Variation ID: 370466 Accession: VCV000370466.11

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 16q24.3 16: 89742803-89742804 (GRCh38) [ NCBI UCSC ] 16: 89809211-89809212 (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	Jan 7, 2017	Jun 17, 2024	Dec 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000135.4:c.3761_3762del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000126.2:p.Glu1254fs	frameshift
NM_000135.4:c.3761_3762delAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000135.2:c.3761_3762del
NM_001286167.3:c.3761_3762del	NP_001273096.1:p.Glu1254fs	frameshift
NC_000016.10:g.89742804TC[3]
NC_000016.9:g.89809212TC[3]
NG_011706.1:g.78848AG[3]
LRG_495:g.78848AG[3]
LRG_495t1:c.3761_3762del

... more HGVS ... less HGVS

Protein change

E1254fs

Other names

Canonical SPDI

NC_000016.10:89742802:CTCTCTCTC:CTCTCTC

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.

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

Links

ClinGen: CA16041802 dbSNP: rs868273545 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.
FANCA		-	-	GRCh38 GRCh37	4167	5325

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.
Fanconi anemia complementation group A	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 19, 2023	RCV000411410.8
See cases	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2020	RCV002252108.2

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.
Pathogenic (Mar 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523596.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PVS1, PS4, PM2 Clinical Features: Seizure (present) , Neurodevelopmental abnormality (present) Geographic origin: Brazil
Pathogenic (Aug 16, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000485796.2 First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 9371798‚ 26799702
Pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811719.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A (X-linked dominant inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003845980.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Publications: PubMed (1) PubMed: 9371798 Comment: A Heterozygous Frameshift variant c.3761_3762delAG in Exon 37 of the FANCA gene that results in the amino acid substitution p.Glu1254fs23 was identified. The observed variant … (more) A Heterozygous Frameshift variant c.3761_3762delAG in Exon 37 of the FANCA gene that results in the amino acid substitution p.Glu1254fs23 was identified. The observed variant novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 370466). This variant was reported among the patients for Fanconi Anemia (Levran O et al., 1997). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Dec 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196028.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 28, 2020)	no assertion criteria provided Method: curation	Fanconi anemia complementation group A Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001425988.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Comment: Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Sue Richards.

Comment:

A Heterozygous Frameshift variant c.3761_3762delAG in Exon 37 of the FANCA gene that results in the amino acid substitution p.Glu1254fs*23 was identified. The observed variant novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 370466). This variant was reported among the patients for Fanconi Anemia (Levran O et al., 1997). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

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
FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients.	Solanki A	PloS one	2016	PMID: 26799702
Sequence variation in the Fanconi anemia gene FAA.	Levran O	Proceedings of the National Academy of Sciences of the United States of America	1997	PMID: 9371798

Text-mined citations for rs868273545 ...

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 Jun 17, 2024

ClinVar Genomic variation as it relates to human health

NM_000135.4(FANCA):c.3761_3762del (p.Glu1254fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs868273545 ...