14-45196265-C-G

Position:

chr14-45196265-C-G

Variant summary

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

The NM_020937.4(FANCM):c.5434C>G(p.Pro1812Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,652 control chromosomes in the GnomAD database, including 10,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1812L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.087 ( 757 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9725 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.37

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=0.0012592673).

BP6

Variant 14-45196265-C-G is Benign according to our data. Variant chr14-45196265-C-G is described in ClinVar as [Benign]. Clinvar id is 261390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.5434C>G	p.Pro1812Ala	missense_variant	21/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10 linkuse as main transcript	c.5434C>G	p.Pro1812Ala	missense_variant	21/23	1	NM_020937.4	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0868

AC:

13205

AN:

152064

Hom.:

758

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.111

GnomAD3 exomes

AF:

0.116

AC:

29247

AN:

251378

Hom.:

1945

AF XY:

0.121

AC XY:

16422

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.124

Gnomad SAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.109

AC:

159686

AN:

1461470

Hom.:

9725

Cov.:

AF XY:

0.112

AC XY:

81710

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0175

Gnomad4 AMR exome

AF:

0.113

Gnomad4 ASJ exome

AF:

0.141

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.123

Gnomad4 NFE exome

AF:

0.103

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.0868

AC:

13206

AN:

152182

Hom.:

757

Cov.:

AF XY:

0.0889

AC XY:

6615

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0221

Gnomad4 AMR

AF:

0.100

Gnomad4 ASJ

AF:

0.136

Gnomad4 EAS

AF:

0.119

Gnomad4 SAS

AF:

0.196

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0973

Hom.:

665

Bravo

AF:

0.0823

TwinsUK

AF:

0.0947

AC:

351

ALSPAC

AF:

0.0955

AC:

368

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.106

AC:

910

ExAC

AF:

0.116

AC:

14054

Asia WGS

AF:

0.133

AC:

461

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.108

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Premature ovarian failure 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2019

- -

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

0.090

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.67

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.034

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.10

MPC

0.087

ClinPred

0.013

GERP RS

3.3

Varity_R

0.081

gMVP

0.24

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