14-45175386-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
spermatogenic failure 28
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

FANCM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.2632G>T	p.Val878Leu	missense_variant	Exon 14 of 23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 link	c.2632G>T	p.Val878Leu	missense_variant	Exon 14 of 23	1	NM_020937.4	ENSP00000267430.5		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

GnomAD2 exomes

AF:

0.149

AC:

33860

AN:

227958

AF XY:

0.145

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 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

African (AFR)

AF:

0.358

AC:

11023

AN:

30772

American (AMR)

AF:

0.166

AC:

6243

AN:

37644

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3497

AN:

24618

East Asian (EAS)

AF:

0.140

AC:

5512

AN:

39308

South Asian (SAS)

AF:

0.185

AC:

14665

AN:

79266

European-Finnish (FIN)

AF:

0.121

AC:

6385

AN:

52606

Middle Eastern (MID)

AF:

0.161

AC:

888

AN:

5516

European-Non Finnish (NFE)

AF:

0.114

AC:

123211

AN:

1077362

Other (OTH)

AF:

0.143

AC:

8325

AN:

58066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

6830

13661

20491

27322

34152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.192

AC:

29154

AN:

152110

Hom.:

3656

Cov.:

AF XY:

0.190

AC XY:

14147

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.355

AC:

14719

AN:

41478

American (AMR)

AF:

0.167

AC:

2554

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

487

AN:

3470

East Asian (EAS)

AF:

0.135

AC:

701

AN:

5178

South Asian (SAS)

AF:

0.188

AC:

905

AN:

4826

European-Finnish (FIN)

AF:

0.108

AC:

1144

AN:

10594

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8042

AN:

67962

Other (OTH)

AF:

0.189

AC:

399

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1145

2290

3434

4579

5724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.139

Hom.:

7211

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spermatogenic failure 28

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.

PhyloP100

0.31

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

Mutation Taster

=100/0

polymorphism (auto)

(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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14-45175386-G-T

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