14-45175386-G-T

Position:

chr14-45175386-G-T

Variant summary

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

The NM_020937.4(FANCM):c.2632G>T(p.Val878Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,557,268 control chromosomes in the GnomAD database, including 16,851 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3656 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13195 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.306

Variant links:

Genes affected

FANCM (HGNC:23168): (FA complementation group M) 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 M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

FANCM 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=0.0020548701).

BP6

Variant 14-45175386-G-T is Benign according to our data. Variant chr14-45175386-G-T is described in ClinVar as [Benign]. Clinvar id is 261383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.2632G>T	p.Val878Leu	missense_variant	14/23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 linkuse as main transcript	c.2632G>T	p.Val878Leu	missense_variant	14/23	1	NM_020937.4	ENSP00000267430	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

29070

AN:

151992

Hom.:

3625

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.135

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.149

AC:

33860

AN:

227958

Hom.:

3000

AF XY:

0.145

AC XY:

17917

AN XY:

123478

show subpopulations

Gnomad AFR exome

AF:

0.355

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.137

Gnomad SAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.128

AC:

179749

AN:

1405158

Hom.:

13195

Cov.:

AF XY:

0.129

AC XY:

90285

AN XY:

699202

show subpopulations

Gnomad4 AFR exome

AF:

0.358

Gnomad4 AMR exome

AF:

0.166

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.140

Gnomad4 SAS exome

AF:

0.185

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.114

Gnomad4 OTH exome

AF:

0.143

GnomAD4 genome

AF:

0.192

AC:

29154

AN:

152110

Hom.:

3656

Cov.:

AF XY:

0.190

AC XY:

14147

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.355

Gnomad4 AMR

AF:

0.167

Gnomad4 ASJ

AF:

0.140

Gnomad4 EAS

AF:

0.135

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.108

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.131

Hom.:

3248

Bravo

AF:

0.201

TwinsUK

AF:

0.111

AC:

412

ALSPAC

AF:

0.112

AC:

433

ESP6500AA

AF:

0.333

AC:

1460

ESP6500EA

AF:

0.119

AC:

1020

ExAC

AF:

0.156

AC:

18878

Asia WGS

AF:

0.169

AC:

590

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Premature ovarian failure 15

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Spermatogenic failure 28

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.81

DANN

Benign

0.098

DEOGEN2

Benign

0.036

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.27

T;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.0

N;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

0.96

N;N;N

REVEL

Benign

0.098

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.93

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.013

MutPred

0.21

Gain of catalytic residue at D876 (P = 0.0031);.;.;

MPC

0.083

ClinPred

0.0037

GERP RS

4.1

Varity_R

0.043

gMVP

0.092

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

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