9-35075741-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_004629.2(FANCG):c.1157C>G(p.Pro386Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P386H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FANCG
NM_004629.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2O:1

Conservation

PhyloP100: 0.207

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group G
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024385482).

BP6

Variant 9-35075741-G-C is Benign according to our data. Variant chr9-35075741-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134360.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCG	NM_004629.2 link	c.1157C>G	p.Pro386Arg	missense_variant	Exon 10 of 14	ENST00000378643.8	NP_004620.1	O15287Q53XM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCG	ENST00000378643.8 link	c.1157C>G	p.Pro386Arg	missense_variant	Exon 10 of 14	1	NM_004629.2	ENSP00000367910.4		O15287

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

128886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000626

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000271

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000161

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000947

AC:

AN:

232370

AF XY:

0.0000866

show subpopulations

Gnomad AFR exome

AF:

0.000552

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000283

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000664

Gnomad OTH exome

AF:

0.000354

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000141

AC:

AN:

460824

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

251034

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

12430

American (AMR)

AF:

0.00

AC:

AN:

35902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13584

East Asian (EAS)

AF:

0.000282

AC:

AN:

17702

South Asian (SAS)

AF:

0.0000148

AC:

AN:

67342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3114

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

258510

Other (OTH)

AF:

0.000289

AC:

AN:

20752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.702

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000186

AC:

AN:

128984

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

AN XY:

61144

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

35202

American (AMR)

AF:

0.00

AC:

AN:

11872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3210

East Asian (EAS)

AF:

0.000271

AC:

AN:

3692

South Asian (SAS)

AF:

0.00

AC:

AN:

3312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.0000161

AC:

AN:

61974

Other (OTH)

AF:

0.00

AC:

AN:

1822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.654

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group G

Uncertain:1Benign:1

Nov 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fanconi anemia

Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 386 of the FANCG protein (p.Pro386Arg). This variant is present in population databases (rs141147618, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FANCG-related conditions. ClinVar contains an entry for this variant (Variation ID: 134360). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FANCG protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Jan 31, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ovarian cancer

Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.3

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.20

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.55

M_CAP

Benign

0.013

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

0.21

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.0

REVEL

Benign

0.032

Sift

Benign

0.24

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.15

MVP

0.36

MPC

0.22

ClinPred

0.023

GERP RS

1.4

Varity_R

0.030

gMVP

0.14

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over