rs61753893

Positions:

chr14-45167125-A-G

Variant summary

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

The ENST00000267430.10(FANCM):c.1964A>G(p.Asn655Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,416 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 32)

Exomes 𝑓: 0.016 ( 248 hom. )

Consequence

FANCM
ENST00000267430.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.410

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=0.002967447).

BP6

Variant 14-45167125-A-G is Benign according to our data. Variant chr14-45167125-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 241315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45167125-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1626/152324) while in subpopulation NFE AF= 0.0182 (1236/68036). AF 95% confidence interval is 0.0173. There are 17 homozygotes in gnomad4. There are 684 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.1964A>G	p.Asn655Ser	missense_variant	11/23	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.1964A>G	p.Asn655Ser	missense_variant	11/23	1	NM_020937.4	ENSP00000267430	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1627

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0106

AC:

2661

AN:

251148

Hom.:

AF XY:

0.0105

AC XY:

1423

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00490

Gnomad FIN exome

AF:

0.00799

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0162

AC:

23653

AN:

1461092

Hom.:

248

Cov.:

AF XY:

0.0158

AC XY:

11488

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00643

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00522

Gnomad4 FIN exome

AF:

0.00857

Gnomad4 NFE exome

AF:

0.0191

Gnomad4 OTH exome

AF:

0.0156

GnomAD4 genome

AF:

0.0107

AC:

1626

AN:

152324

Hom.:

Cov.:

AF XY:

0.00918

AC XY:

684

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00308

Gnomad4 AMR

AF:

0.00706

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00584

Gnomad4 NFE

AF:

0.0182

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0101

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0184

AC:

158

ExAC

AF:

0.0105

AC:

1277

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	This variant is associated with the following publications: (PMID: 29351780) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.079

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

DANN

Benign

0.87

DEOGEN2

Benign

0.051

.;T;.;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.41

N;N;N;N

REVEL

Benign

0.070

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.83

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.047

MPC

0.068

ClinPred

0.0018

GERP RS

-1.0

Varity_R

0.029

gMVP

0.25

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