14-45181697-A-G

Position:

chr14-45181697-A-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.4378A>G(p.Ile1460Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,601,576 control chromosomes in the GnomAD database, including 9,716 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 Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 718 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8998 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.165

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=0.0013127029).

BP6

Variant 14-45181697-A-G is Benign according to our data. Variant chr14-45181697-A-G is described in ClinVar as [Benign]. Clinvar id is 261386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.4378A>G	p.Ile1460Val	missense_variant	16/23	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.4378A>G	p.Ile1460Val	missense_variant	16/23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0850

AC:

12925

AN:

152120

Hom.:

720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.0984

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.109

GnomAD3 exomes

AF:

0.113

AC:

28015

AN:

248340

Hom.:

1789

AF XY:

0.117

AC XY:

15672

AN XY:

134422

show subpopulations

Gnomad AFR exome

AF:

0.0194

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.123

Gnomad SAS exome

AF:

0.185

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.106

AC:

152926

AN:

1449338

Hom.:

8998

Cov.:

AF XY:

0.108

AC XY:

78171

AN XY:

721746

show subpopulations

Gnomad4 AFR exome

AF:

0.0172

Gnomad4 AMR exome

AF:

0.112

Gnomad4 ASJ exome

AF:

0.137

Gnomad4 EAS exome

AF:

0.122

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.119

Gnomad4 NFE exome

AF:

0.0996

Gnomad4 OTH exome

AF:

0.108

GnomAD4 genome

AF:

0.0849

AC:

12925

AN:

152238

Hom.:

718

Cov.:

AF XY:

0.0868

AC XY:

6457

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0218

Gnomad4 AMR

AF:

0.0987

Gnomad4 ASJ

AF:

0.132

Gnomad4 EAS

AF:

0.119

Gnomad4 SAS

AF:

0.182

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.103

Gnomad4 OTH

AF:

0.108

Alfa

AF:

0.0989

Hom.:

1311

Bravo

AF:

0.0810

TwinsUK

AF:

0.0922

AC:

342

ALSPAC

AF:

0.0937

AC:

361

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.103

AC:

887

ExAC

AF:

0.111

AC:

13510

Asia WGS

AF:

0.126

AC:

438

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	- -
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

- -

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

0.060

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.0

DANN

Benign

0.26

DEOGEN2

Benign

0.056

T;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.15

N;N;N

REVEL

Benign

0.014

Sift

Benign

0.98

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.015

B;.;.

Vest4

0.065

MPC

0.071

ClinPred

0.000013

GERP RS

-1.2

Varity_R

0.032

gMVP

0.055

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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