NM_020937.4:c.229A>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.229A>G(p.Thr77Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,858 control chromosomes in the GnomAD database, including 235 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T77T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 33 hom., cov: 32)

Exomes 𝑓: 0.015 ( 202 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.32

Publications

17 publications found

Variant links:

COSMIC-nc: COSV53531849

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=0.0024504364).

BP6

Variant 14-45136260-A-G is Benign according to our data. Variant chr14-45136260-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0188 (2858/151978) while in subpopulation AFR AF = 0.0378 (1568/41450). AF 95% confidence interval is 0.0363. There are 33 homozygotes in GnomAd4. There are 1270 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.229A>G	p.Thr77Ala	missense_variant	Exon 1 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.229A>G	p.Thr77Ala	missense_variant	Exon 1 of 23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2851

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0377

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00312

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0116

AC:

2902

AN:

251226

AF XY:

0.0112

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000697

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0147

AC:

21457

AN:

1461880

Hom.:

202

Cov.:

AF XY:

0.0143

AC XY:

10366

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0362

AC:

1213

AN:

33480

American (AMR)

AF:

0.0127

AC:

567

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00381

AC:

329

AN:

86258

European-Finnish (FIN)

AF:

0.00125

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0164

AC:

18208

AN:

1112010

Other (OTH)

AF:

0.0151

AC:

912

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1321

2643

3964

5286

6607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.0188

AC:

2858

AN:

151978

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1270

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.0378

AC:

1568

AN:

41450

American (AMR)

AF:

0.0154

AC:

235

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00312

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0142

AC:

964

AN:

67964

Other (OTH)

AF:

0.0227

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

149

299

448

598

747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0150

Hom.:

Bravo

AF:

0.0202

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.0350

AC:

154

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.0124

AC:

1507

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Mar 26, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 25, 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, 19737859) -

Premature ovarian failure 15

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Jan 30, 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

0.060

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.6

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.065

.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.46

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;L

PhyloP100

-1.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.95

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.079

MPC

0.083

ClinPred

0.021

GERP RS

-11

PromoterAI

0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.049

gMVP

0.26

Mutation Taster

=98/2

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