rs45547534

Positions:

chr14-45137184-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.624A>G(p.Ile208Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,613,676 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 11 hom., cov: 32)

Exomes 𝑓: 0.015 ( 183 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0190

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=0.0072793067).

BP6

Variant 14-45137184-A-G is Benign according to our data. Variant chr14-45137184-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 241326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45137184-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1601/152300) while in subpopulation NFE AF= 0.0165 (1121/68024). AF 95% confidence interval is 0.0157. There are 11 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.624A>G	p.Ile208Met	missense_variant	2/23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 link	c.624A>G	p.Ile208Met	missense_variant	2/23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1601

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0102

AC:

2566

AN:

251204

Hom.:

AF XY:

0.0106

AC XY:

1437

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00656

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.00559

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.0146

AC:

21277

AN:

1461376

Hom.:

183

Cov.:

AF XY:

0.0145

AC XY:

10548

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00707

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.00593

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0105

AC:

1601

AN:

152300

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

707

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.0134

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00849

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.0165

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0107

AC:

1296

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2017	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCM p.Ile208Met variant was identified in 6 of 854 proband chromosomes (frequency: 0.007) from individuals with breast or ovarian cancer (Nguyen-Dumont_2018_PMID:29351780). The variant was identified in dbSNP (ID: rs45547534) and ClinVar (classified as benign by ARUP Laboratories and Invitae). The variant was not identified in the Cosmic database and in control databases in 2619 of 268068 chromosomes (22 homozygous) at a frequency of 0.00977 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1778 of 118106 chromosomes (freq: 0.01505), South Asian in 313 of 30522 chromosomes (freq: 0.01025), Other in 63 of 6702 chromosomes (freq: 0.0094), Latino in 237 of 35106 chromosomes (freq: 0.006751), European (Finnish) in 136 of 24908 chromosomes (freq: 0.00546), Ashkenazi Jewish in 37 of 9860 chromosomes (freq: 0.003753) and African in 55 of 23612 chromosomes (freq: 0.002329), but was not observed in the East Asian population. The p.Ile208 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 16, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FANCM: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2021	- -
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

0.27

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T;.

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

M;M;M

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.90

P;D;.

Vest4

0.33

MPC

0.45

ClinPred

0.062

GERP RS

0.0078

Varity_R

0.55

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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