14-45175503-A-G

Position:

chr14-45175503-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.2749A>G(p.Ile917Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,004 control chromosomes in the GnomAD database, including 39 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 0.0029 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 34 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.116

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=0.0037210584).

BP6

Variant 14-45175503-A-G is Benign according to our data. Variant chr14-45175503-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45175503-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00286 (435/152318) while in subpopulation AMR AF= 0.0206 (315/15290). AF 95% confidence interval is 0.0187. There are 5 homozygotes in gnomad4. There are 253 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.2749A>G	p.Ile917Val	missense_variant	14/23	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.2749A>G	p.Ile917Val	missense_variant	14/23	1	NM_020937.4	ENSP00000267430	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

434

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0154

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00593

AC:

1484

AN:

250232

Hom.:

AF XY:

0.00466

AC XY:

631

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0161

Gnomad SAS exome

AF:

0.000361

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00163

AC:

2375

AN:

1460686

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1042

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0317

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0181

Gnomad4 SAS exome

AF:

0.000430

Gnomad4 FIN exome

AF:

0.00144

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

AF:

0.00286

AC:

435

AN:

152318

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.0206

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0156

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000842

Hom.:

Bravo

AF:

0.00426

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00473

AC:

574

Asia WGS

AF:

0.00751

AC:

AN:

3474

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2021	- -

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

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.038

DANN

Benign

0.23

DEOGEN2

Benign

0.042

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.36

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.92

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.080

N;N;N

REVEL

Benign

0.0090

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.96

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.029

MVP

0.15

MPC

0.071

ClinPred

0.00058

GERP RS

-1.9

Varity_R

0.019

gMVP

0.092

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