14-45196265-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020937.4(FANCM):c.5434C>G(p.Pro1812Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,652 control chromosomes in the GnomAD database, including 10,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1812L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.087 ( 757 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9725 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.37

Publications

28 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012592673).

BP6

Variant 14-45196265-C-G is Benign according to our data. Variant chr14-45196265-C-G is described in ClinVar as Benign. ClinVar VariationId is 261390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.5434C>G	p.Pro1812Ala	missense_variant	Exon 21 of 23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 link	c.5434C>G	p.Pro1812Ala	missense_variant	Exon 21 of 23	1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes

AF:

0.0868

AC:

13205

AN:

152064

Hom.:

758

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.111

GnomAD2 exomes

AF:

0.116

AC:

29247

AN:

251378

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.109

AC:

159686

AN:

1461470

Hom.:

9725

Cov.:

AF XY:

0.112

AC XY:

81710

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0175

AC:

585

AN:

33466

American (AMR)

AF:

0.113

AC:

5055

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

3686

AN:

26126

East Asian (EAS)

AF:

0.123

AC:

4870

AN:

39682

South Asian (SAS)

AF:

0.200

AC:

17272

AN:

86250

European-Finnish (FIN)

AF:

0.123

AC:

6573

AN:

53420

Middle Eastern (MID)

AF:

0.136

AC:

783

AN:

5768

European-Non Finnish (NFE)

AF:

0.103

AC:

114127

AN:

1111672

Other (OTH)

AF:

0.112

AC:

6735

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

7824

15648

23472

31296

39120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4284

8568

12852

17136

21420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0868

AC:

13206

AN:

152182

Hom.:

757

Cov.:

AF XY:

0.0889

AC XY:

6615

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0221

AC:

918

AN:

41534

American (AMR)

AF:

0.100

AC:

1534

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

473

AN:

3472

East Asian (EAS)

AF:

0.119

AC:

617

AN:

5178

South Asian (SAS)

AF:

0.196

AC:

946

AN:

4820

European-Finnish (FIN)

AF:

0.111

AC:

1171

AN:

10568

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7128

AN:

68004

Other (OTH)

AF:

0.111

AC:

234

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

580

1160

1741

2321

2901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0973

Hom.:

665

Bravo

AF:

0.0823

TwinsUK

AF:

0.0947

AC:

351

ALSPAC

AF:

0.0955

AC:

368

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.106

AC:

910

ExAC

AF:

0.116

AC:

14054

Asia WGS

AF:

0.133

AC:

461

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.108

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 13, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Premature ovarian failure 15

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spermatogenic failure 28

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.67

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

1.4

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.034

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.10

MPC

0.087

ClinPred

0.013

GERP RS

3.3

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.081

gMVP

0.24

Mutation Taster

=100/0

polymorphism (auto)

(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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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