chr14-45159275-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_020937.4(FANCM):c.1576C>G(p.Leu526Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,609,804 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 0.954

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020171225).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00141 (214/152170) while in subpopulation AMR AF= 0.0055 (84/15270). AF 95% confidence interval is 0.00455. There are 1 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.1576C>G	p.Leu526Val	missense_variant	Exon 9 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.1576C>G	p.Leu526Val	missense_variant	Exon 9 of 23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00551

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000980

AC:

245

AN:

250030

Hom.:

AF XY:

0.000902

AC XY:

122

AN XY:

135290

show subpopulations

Gnomad AFR exome

AF:

0.000374

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00176

AC:

2559

AN:

1457634

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1211

AN XY:

725360

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00182

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000469

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.000963

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152170

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00550

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000945

Gnomad4 NFE

AF:

0.00153

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00156

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000890

AC:

108

EpiCase

AF:

0.00159

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCM: PM2, BP4 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast or other cancers, but also in unaffected controls (PMID: 28881617, 19737859, 34646395, 29351780, 30426508); This variant is associated with the following publications: (PMID: 30426508, 19737859, 29351780, 28881617, 32268276, 29641532, 34646395, 36980780) -

Spermatogenic failure 28;C4748170:Premature ovarian failure 15

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 06, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Spermatogenic failure 28

Uncertain:1

Jun 05, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Fanconi anemia

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FANCM-related disorder

Benign:1

Apr 26, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.8

L;L;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Benign

0.052

Sift

Benign

0.033

D;D;D;D

Sift4G

Uncertain

0.039

D;D;D;D

Polyphen

0.0020

B;B;.;.

Vest4

0.27

MVP

0.59

MPC

0.090

ClinPred

0.031

GERP RS

3.4

Varity_R

0.14

gMVP

0.55

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