rs2237857

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004629.2(FANCG):c.890C>T(p.Thr297Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,128 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 170 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 439 hom. )

Consequence

FANCG
NM_004629.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:16O:1

Conservation

PhyloP100: 1.27

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:

FANCG (HGNC:):

FANCG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016728342).

BP6

Variant 9-35076758-G-A is Benign according to our data. Variant chr9-35076758-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35076758-G-A is described in Lovd as [Benign]. Variant chr9-35076758-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCG	NM_004629.2 linkuse as main transcript	c.890C>T	p.Thr297Ile	missense_variant	7/14	ENST00000378643.8	NP_004620.1	O15287Q53XM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCG	ENST00000378643.8 linkuse as main transcript	c.890C>T	p.Thr297Ile	missense_variant	7/14	1	NM_004629.2	ENSP00000367910.4		O15287

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4480

AN:

152116

Hom.:

171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0878

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0507

Gnomad SAS

AF:

0.0497

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0154

AC:

3867

AN:

251494

Hom.:

117

AF XY:

0.0152

AC XY:

2068

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0907

Gnomad AMR exome

AF:

0.00503

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0298

Gnomad SAS exome

AF:

0.0474

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00945

GnomAD4 exome

AF:

0.00859

AC:

12564

AN:

1461894

Hom.:

439

Cov.:

AF XY:

0.00927

AC XY:

6740

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0961

Gnomad4 AMR exome

AF:

0.00539

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.0761

Gnomad4 SAS exome

AF:

0.0434

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0294

AC:

4481

AN:

152234

Hom.:

170

Cov.:

AF XY:

0.0302

AC XY:

2249

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0876

Gnomad4 AMR

AF:

0.0120

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0508

Gnomad4 SAS

AF:

0.0495

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00153

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.00698

Hom.:

Bravo

AF:

0.0321

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0815

AC:

359

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.0177

AC:

2150

Asia WGS

AF:

0.0590

AC:

203

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Fanconi anemia complementation group G

Pathogenic:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 07, 2011	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Fanconi anemia

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	This variant is associated with the following publications: (PMID: 11093276, 27153395, 27884173, 11438206, 24728327, 20981092, 17010390) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Amyotrophic Lateral Sclerosis, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

FANCG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inclusion Body Myopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.14

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

REVEL

Benign

0.043

Sift

Benign

0.057

Sift4G

Uncertain

0.041

Polyphen

0.28

Vest4

0.056

MPC

0.35

ClinPred

0.0082

GERP RS

4.5

Varity_R

0.035

gMVP

0.095

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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