14-45196458-A-G

Position:

chr14-45196458-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020937.4(FANCM):c.5627A>G(p.Asn1876Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,614,114 control chromosomes in the GnomAD database, including 741 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 59 hom., cov: 32)

Exomes 𝑓: 0.028 ( 682 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.115

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:

FANCM (HGNC:):

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=0.0030958652).

BP6

Variant 14-45196458-A-G is Benign according to our data. Variant chr14-45196458-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45196458-A-G is described in Lovd as [Benign]. Variant chr14-45196458-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.021 (3195/152338) while in subpopulation NFE AF= 0.0315 (2146/68028). AF 95% confidence interval is 0.0304. There are 59 homozygotes in gnomad4. There are 1529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.5627A>G	p.Asn1876Ser	missense_variant	21/23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 linkuse as main transcript	c.5627A>G	p.Asn1876Ser	missense_variant	21/23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3196

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.00962

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.0498

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0315

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0210

AC:

5290

AN:

251400

Hom.:

AF XY:

0.0210

AC XY:

2858

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.00755

Gnomad ASJ exome

AF:

0.0167

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00686

Gnomad FIN exome

AF:

0.0473

Gnomad NFE exome

AF:

0.0300

Gnomad OTH exome

AF:

0.0225

GnomAD4 exome

AF:

0.0275

AC:

40227

AN:

1461776

Hom.:

682

Cov.:

AF XY:

0.0270

AC XY:

19654

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00475

Gnomad4 AMR exome

AF:

0.00776

Gnomad4 ASJ exome

AF:

0.0171

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00700

Gnomad4 FIN exome

AF:

0.0484

Gnomad4 NFE exome

AF:

0.0312

Gnomad4 OTH exome

AF:

0.0223

GnomAD4 genome

AF:

0.0210

AC:

3195

AN:

152338

Hom.:

Cov.:

AF XY:

0.0205

AC XY:

1529

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00452

Gnomad4 AMR

AF:

0.00961

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0498

Gnomad4 NFE

AF:

0.0315

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0271

Hom.:

113

Bravo

AF:

0.0174

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0292

AC:

251

ExAC

AF:

0.0210

AC:

2556

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0288

EpiControl

AF:

0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2021	This variant is associated with the following publications: (PMID: 19737859, 29351780) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Premature ovarian failure 15

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.41

DANN

Benign

0.72

DEOGEN2

Benign

0.19

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Benign

0.019

Sift

Benign

0.17

T;T;T;T

Sift4G

Uncertain

0.060

T;T;T;T

Polyphen

0.010

B;.;.;.

Vest4

0.057

MPC

0.072

ClinPred

0.0018

GERP RS

-4.7

Varity_R

0.16

gMVP

0.19

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