9-35074172-GGACGGATCCA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_004629.2(FANCG):c.1795_1804del(p.Trp599ProfsTer49) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000539 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

FANCG
NM_004629.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.60

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 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0396 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-35074172-GGACGGATCCA-G is Pathogenic according to our data. Variant chr9-35074172-GGACGGATCCA-G is described in ClinVar as [Pathogenic]. Clinvar id is 6718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35074172-GGACGGATCCA-G 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.1795_1804del	p.Trp599ProfsTer49	frameshift_variant	14/14	ENST00000378643.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCG	ENST00000378643.8 linkuse as main transcript	c.1795_1804del	p.Trp599ProfsTer49	frameshift_variant	14/14	1	NM_004629.2	P2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152236

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461878

Hom.:

AF XY:

0.0000495

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000683

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group G

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 27, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 31, 2020	- -

Fanconi anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2023

This sequence change results in a frameshift in the FANCG gene (p.Trp599Profs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the FANCG protein and extend the protein by 24 additional amino acid residues. This variant is present in population databases (rs776937138, gnomAD 0.007%). This frameshift has been observed in individual(s) with Fanconi anemia (PMID: 12552564). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1794_1803del10 or c.1794_1803del. ClinVar contains an entry for this variant (Variation ID: 6718). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2022

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 24 amino acids are lost and replaced with 48 incorrect amino acids; Also known as 1794_1803del10; This variant is associated with the following publications: (PMID: 12552564, 29625052, 35929646) -

FANCG-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The FANCG c.1795_1804del10 variant is predicted to result in a frameshift and premature protein termination (p.Trp599Profs*49). This variant, referred to as c.1794_1803del, was reported in the homozygous state and along with a second FANCG mutation in multiple individuals with Fanconi anemia (Auerbach et al. 2003. PubMed ID: 12552564). This variant is the most common FANCG mutation in the Northern European population (Auerbach et al. 2003. PubMed ID: 12552564). This variant has also been reported within the lung squamous cell carcinoma cohort when looking at predisposition variants in cancer (Huang et al. 2018. PubMed ID: 29625052; Chan et al. 2021. PubMed ID: 35929646). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Frameshift variants in FANCG are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Other links and lift over