9-35079505-G-A

Position:

chr9-35079505-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_004629.2(FANCG):c.20C>T(p.Ser7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,128 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 34 hom. )

Consequence

FANCG
NM_004629.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: -0.0400

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 Benign. Variant got -11 ACMG points.

PM1

In a mutagenesis_site Loss of BRCA2-, FANCD2- and XRCC3-binding. No effect on complex formation with FANCA and FANCF. (size 0) in uniprot entity FANCG_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0034295917).

BP6

Variant 9-35079505-G-A is Benign according to our data. Variant chr9-35079505-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134358.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00172 (262/152332) while in subpopulation SAS AF= 0.00995 (48/4824). AF 95% confidence interval is 0.00771. There are 3 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCG	NM_004629.2 linkuse as main transcript	c.20C>T	p.Ser7Phe	missense_variant	1/14	ENST00000378643.8	NP_004620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCG	ENST00000378643.8 linkuse as main transcript	c.20C>T	p.Ser7Phe	missense_variant	1/14	1	NM_004629.2	ENSP00000367910	P2

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

263

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00339

AC:

847

AN:

249940

Hom.:

AF XY:

0.00362

AC XY:

490

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.0381

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00725

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00192

AC:

2801

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1551

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.0374

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00716

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000698

Gnomad4 OTH exome

AF:

0.00479

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152332

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00995

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000955

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00326

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00297

AC:

360

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group G

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 27, 2018	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

FANCG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.062

Sift

Uncertain

0.028

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.12

B;.

Vest4

0.18

MVP

0.82

MPC

0.24

ClinPred

0.0053

GERP RS

2.0

Varity_R

0.028

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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