9-35075742-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004629.2(FANCG):c.1156C>A(p.Pro386Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 576,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P386R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000079 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

FANCG
NM_004629.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.799

Publications

2 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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033287406).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004629.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	NM_004629.2	MANE Select	c.1156C>A	p.Pro386Thr	missense	Exon 10 of 14	NP_004620.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCG	ENST00000378643.8	TSL:1 MANE Select	c.1156C>A	p.Pro386Thr	missense	Exon 10 of 14	ENSP00000367910.4
FANCG	ENST00000425676.5	TSL:1	n.*632C>A		non_coding_transcript_exon	Exon 9 of 13	ENSP00000412793.1
FANCG	ENST00000425676.5	TSL:1	n.*632C>A		3_prime_UTR	Exon 9 of 13	ENSP00000412793.1

Frequencies

GnomAD3 genomes

AF:

0.00000790

AC:

AN:

126538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000275

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

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

232908

AF XY:

0.00000785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000400

AC:

AN:

450112

Hom.:

Cov.:

AF XY:

0.0000369

AC XY:

AN XY:

244026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

12276

American (AMR)

AF:

0.00

AC:

AN:

35902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13482

East Asian (EAS)

AF:

0.0000578

AC:

AN:

17300

South Asian (SAS)

AF:

0.0000298

AC:

AN:

67224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3102

European-Non Finnish (NFE)

AF:

0.0000602

AC:

AN:

249138

Other (OTH)

AF:

0.00

AC:

AN:

20358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000222083), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.314

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

AF:

0.00000790

AC:

AN:

126622

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

59744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34056

American (AMR)

AF:

0.00

AC:

AN:

11638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3198

East Asian (EAS)

AF:

0.000276

AC:

AN:

3628

South Asian (SAS)

AF:

0.00

AC:

AN:

3256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

228

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61672

Other (OTH)

AF:

0.00

AC:

AN:

1826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.2

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.093

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.60

M_CAP

Benign

0.0065

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.80

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.83

REVEL

Benign

0.054

Sift

Benign

1.0

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.14

MutPred

0.27

Gain of phosphorylation at P386 (P = 0.0092)

MVP

0.33

MPC

0.24

ClinPred

0.015

GERP RS

1.4

Varity_R

0.020

gMVP

0.16

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over