NM_020937.4:c.1964A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020937.4(FANCM):c.1964A>G(p.Asn655Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,416 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 32)

Exomes 𝑓: 0.016 ( 248 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.410

Publications

12 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=0.002967447).

BP6

Variant 14-45167125-A-G is Benign according to our data. Variant chr14-45167125-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1626/152324) while in subpopulation NFE AF = 0.0182 (1236/68036). AF 95% confidence interval is 0.0173. There are 17 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.1964A>G	p.Asn655Ser	missense_variant	Exon 11 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.1964A>G	p.Asn655Ser	missense_variant	Exon 11 of 23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1627

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0106

AC:

2661

AN:

251148

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00799

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0162

AC:

23653

AN:

1461092

Hom.:

248

Cov.:

AF XY:

0.0158

AC XY:

11488

AN XY:

726906

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33462

American (AMR)

AF:

0.00523

AC:

234

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00643

AC:

168

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39668

South Asian (SAS)

AF:

0.00522

AC:

450

AN:

86244

European-Finnish (FIN)

AF:

0.00857

AC:

458

AN:

53414

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0191

AC:

21274

AN:

1111312

Other (OTH)

AF:

0.0156

AC:

940

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1034

2068

3101

4135

5169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.0107

AC:

1626

AN:

152324

Hom.:

Cov.:

AF XY:

0.00918

AC XY:

684

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41578

American (AMR)

AF:

0.00706

AC:

108

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00584

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1236

AN:

68036

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0151

Hom.:

Bravo

AF:

0.0101

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0184

AC:

158

ExAC

AF:

0.0105

AC:

1277

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 14, 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

- -

not provided

Benign:2

Mar 01, 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) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.051

.;T;.;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;N;.;.

PhyloP100

-0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.41

N;N;N;N

REVEL

Benign

0.070

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.83

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.047

MPC

0.068

ClinPred

0.0018

GERP RS

-1.0

Varity_R

0.029

gMVP

0.25

Mutation Taster

=100/0

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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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