chr14-45189246-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020937.4(FANCM):c.5224A>G(p.Ile1742Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,072 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0081 ( 10 hom., cov: 32)

Exomes 𝑓: 0.011 ( 108 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.432

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
spermatogenic failure 28
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

FANCM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002847463).

BP6

Variant 14-45189246-A-G is Benign according to our data. Variant chr14-45189246-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241324.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00813 (1239/152310) while in subpopulation NFE AF = 0.0123 (838/68024). AF 95% confidence interval is 0.0116. There are 10 homozygotes in GnomAd4. There are 607 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.5224A>G	p.Ile1742Val	missense_variant	Exon 20 of 23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 link	c.5224A>G	p.Ile1742Val	missense_variant	Exon 20 of 23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.00813

AC:

1237

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00752

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00864

AC:

2169

AN:

251052

AF XY:

0.00909

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00604

Gnomad ASJ exome

AF:

0.0236

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00735

Gnomad NFE exome

AF:

0.0122

Gnomad OTH exome

AF:

0.00947

GnomAD4 exome

AF:

0.0110

AC:

16051

AN:

1461762

Hom.:

108

Cov.:

AF XY:

0.0109

AC XY:

7944

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33476

American (AMR)

AF:

0.00660

AC:

295

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0221

AC:

577

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00304

AC:

262

AN:

86258

European-Finnish (FIN)

AF:

0.00618

AC:

330

AN:

53416

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0124

AC:

13808

AN:

1111910

Other (OTH)

AF:

0.0102

AC:

618

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

847

1694

2540

3387

4234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00813

AC:

1239

AN:

152310

Hom.:

Cov.:

AF XY:

0.00815

AC XY:

607

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41558

American (AMR)

AF:

0.00751

AC:

115

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00828

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

838

AN:

68024

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00835

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0141

AC:

121

ExAC

AF:

0.00840

AC:

1020

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 23, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FANCM: BP4, BS1, BS2 -

Mar 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29351780, 28202063) -

Spermatogenic failure 28

Uncertain:1

Jul 24, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Fanconi anemia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 24, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.028

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.042

T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;.;.

PhyloP100

-0.43

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.020

N;N;N

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.015

MVP

0.39

MPC

0.071

ClinPred

0.00054

GERP RS

-2.3

Varity_R

0.018

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(source)

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

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chr14-45189246-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over