rs61746895

Positions:

chr14-45136260-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.229A>G(p.Thr77Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,858 control chromosomes in the GnomAD database, including 235 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T77T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 33 hom., cov: 32)

Exomes 𝑓: 0.015 ( 202 hom. )

Consequence

FANCM
ENST00000267430.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.32

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=0.0024504364).

BP6

Variant 14-45136260-A-G is Benign according to our data. Variant chr14-45136260-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45136260-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0188 (2858/151978) while in subpopulation AFR AF= 0.0378 (1568/41450). AF 95% confidence interval is 0.0363. There are 33 homozygotes in gnomad4. There are 1270 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.229A>G	p.Thr77Ala	missense_variant	1/23	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.229A>G	p.Thr77Ala	missense_variant	1/23	1	NM_020937.4	ENSP00000267430	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2851

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0377

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00312

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0116

AC:

2902

AN:

251226

Hom.:

AF XY:

0.0112

AC XY:

1516

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00349

Gnomad FIN exome

AF:

0.000697

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0147

AC:

21457

AN:

1461880

Hom.:

202

Cov.:

AF XY:

0.0143

AC XY:

10366

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0362

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.00360

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00381

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.0164

Gnomad4 OTH exome

AF:

0.0151

GnomAD4 genome

AF:

0.0188

AC:

2858

AN:

151978

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1270

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0378

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00312

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.0142

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0146

Hom.:

Bravo

AF:

0.0202

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.0350

AC:

154

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.0124

AC:

1507

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0143

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, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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 25, 2021	This variant is associated with the following publications: (PMID: 29351780, 19737859) -
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

1.6

DANN

Benign

0.48

DEOGEN2

Benign

0.065

.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.46

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.95

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.079

MPC

0.083

ClinPred

0.021

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.049

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