rs587776640

chr9-35077266-TGGCGGTA-Tchr9-35077266-TGGCGGTA-TGGCGGTAGGCGGTA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004629.2(FANCG):c.637_643del(p.Tyr213LysfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000929 in 1,614,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FANCG
NM_004629.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.92

Variant links:

Genes affected

FANCG (HGNC:3588): (FA complementation group G) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group G. [provided by RefSeq, Jul 2008]

FANCG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-35077266-TGGCGGTA-T is Pathogenic according to our data. Variant chr9-35077266-TGGCGGTA-T is described in ClinVar as [Pathogenic]. Clinvar id is 6719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35077266-TGGCGGTA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCG	NM_004629.2 linkuse as main transcript	c.637_643del	p.Tyr213LysfsTer6	frameshift_variant	5/14	ENST00000378643.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCG	ENST00000378643.8 linkuse as main transcript	c.637_643del	p.Tyr213LysfsTer6	frameshift_variant	5/14	1	NM_004629.2	P2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461880

Hom.:

AF XY:

0.00000963

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group G

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Apr 25, 2015	Our laboratory reported dual molecular diagnoses in FANCG (NM_004629.1, c.637_643del) and G6PD (NM_001042351.1, c.563C>T) in one individual with reported features of intrauterine growth restriction, profound motor and speech delay, intellectual disability, macrocephaly, progressive hydrocephalus, congenital occipital encephalocele, bilateral sensorineural hearing loss, short stature, dysmorphic features, vision loss, congenital right unilateral hypoplasia of depressor anguli oris, feeding difficulties, hypertonia in four extremities, hyperreflexia, joint stiffness, wound dehiscence, and G6PD deficiency. The apparently homozygous c.637_643del (p.Y213fs) FANCG variant has been reported as disease causing (OMIM:602956.0008; PMID 15657175). An affected sibling, who had features consistent with Fanconi anemia, was also homozygous for this variant. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Apr 03, 2024	This sequence change creates a premature translational stop signal (p.Tyr213Lysfs6) in the FANCG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCG are known to be pathogenic (PMID: 12552564). This variant is present in population databases (rs587776640, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Fanconi anemia (FA) (PMID: 15657175, 24136620, 26968956). It is commonly reported in individuals of South African ancestry (PMID: 15657175, 24136620, 26968956). ClinVar contains an entry for this variant (Variation ID: 6719). For these reasons, this variant has been classified as Pathogenic.This sequence change creates a premature translational stop signal (p.Tyr213Lysfs6) in the FANCG gene. It is expected to result in an absent or disrupted protein product. Loss-offunction variants in FANCG are known to be pathogenic (PMID: 12552564). This variant is present in population databases (rs587776640, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Fanconi anemia (FA) (PMID: 15657175, 24136620, 26968956). It is commonly reported in individuals of South African ancestry (PMID: 15657175, 24136620, 26968956). ClinVar contains an entry for this variant (Variation ID: 6719). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 10, 2021	- -

Fanconi anemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2023	This sequence change creates a premature translational stop signal (p.Tyr213Lysfs*6) in the FANCG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCG are known to be pathogenic (PMID: 12552564). This variant is present in population databases (rs587776640, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Fanconi anemia (FA) (PMID: 15657175, 24136620, 26968956). It is commonly reported in individuals of South African ancestry (PMID: 15657175, 24136620, 26968956). ClinVar contains an entry for this variant (Variation ID: 6719). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Tyr213LysfsX6 or c.637_643delTACCGCC variant in FANCG has been reported in the homozygous state in more than 50 individuals with Fanconi anemia (FA) (Morgan N. 2005 PMID: 15657175, Feben C. 2014 PMID: 24136620, Ghazwani Y. 2016 PMID: 26968956). This variand was identified in 0.006% (1/16256) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant is reported in ClinVar (variation ID: 6719). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 213 and leads to a premature termination codon 6 amino acids downstream. Loss of function of the FANCG gene is an established disease mechanism in autosomal recessive FA. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Fanconi anemia. ACMG/AMP criteria applied: PVS1, PS4, PM2_Supporting. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate no detectable FANCG protein in lymphoblastoid cell lines from individuals homozygous for this variant (Morgan et al., 2005); Common pathogenic variant in individual of black South African background, with more than 80% of affected individuals carrying this variant (Morgan et al., 2005; Feben et al., 2015); This variant is associated with the following publications: (PMID: 24300640, 25477267, 24136620, 15657175, 26968956, 27959697, 11126723, 29843852, 26596371, 26962299, 29154021, 28185119, 32529760, 27535533) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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