chr14-45175613-A-C

Position:

chr14-45175613-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020937.4(FANCM):c.2859A>C(p.Lys953Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,613,606 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 0.685

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=0.011752397).

BP6

Variant 14-45175613-A-C is Benign according to our data. Variant chr14-45175613-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313209.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}. Variant chr14-45175613-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.2859A>C	p.Lys953Asn	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.2859A>C	p.Lys953Asn	missense_variant	14/23	1	NM_020937.4	ENSP00000267430	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00110

AC:

275

AN:

249790

Hom.:

AF XY:

0.00105

AC XY:

142

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00201

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.00194

AC:

2839

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1343

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.00238

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152294

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00112

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00111

AC:

135

EpiCase

AF:

0.00175

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, colon, and other cancers (PMID: 27498913, 27713038, 28678401, 28881617, 29351780, 32522261, 34326862); This variant is associated with the following publications: (PMID: 27713038, 28678401, 29351780, 28881617, 27498913, 35495172, 32522261, 34326862, 38093606) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	FANCM: BP4, BS2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 22, 2020

DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.2859A>C, in exon 14 that results in an amino acid change, p.Lys953Asn. This sequence change does not appear to have been previously described in patients with FANCM-related disorders and has been described in the gnomAD database with a low population frequency of 0.19% in the non-Finnish European subpopulation (dbSNP rs142864437). The p.Lys953Asn change affects a poorly conserved amino acid residue located in a domain of the FANCM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys953Asn substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys953Asn change remains unknown at this time. -

Spermatogenic failure 28;C4748170:Premature ovarian failure 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hepatoblastoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

- -

Spermatogenic failure 28

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 11, 2022

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

Fanconi anemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

FANCM-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

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). -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.038

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

N;N;D

REVEL

Benign

0.085

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.060

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.41

MutPred

0.32

Loss of ubiquitination at K953 (P = 0.0027);.;.;

MVP

0.53

MPC

0.50

ClinPred

0.039

GERP RS

1.2

Varity_R

0.15

gMVP

0.26

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