14-45181697-A-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.4378A>G(p.Ile1460Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,601,576 control chromosomes in the GnomAD database, including 9,716 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1460L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.085 ( 718 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8998 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.165

Publications

22 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=0.0013127029).

BP6

Variant 14-45181697-A-G is Benign according to our data. Variant chr14-45181697-A-G is described in ClinVar as Benign. ClinVar VariationId is 261386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020937.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.4378A>G	p.Ile1460Val	missense	Exon 16 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.4300A>G	p.Ile1434Val	missense	Exon 15 of 22	NP_001295062.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCM	ENST00000267430.10	TSL:1 MANE Select	c.4378A>G	p.Ile1460Val	missense	Exon 16 of 23	ENSP00000267430.5
FANCM	ENST00000542564.6	TSL:1	c.4300A>G	p.Ile1434Val	missense	Exon 15 of 22	ENSP00000442493.2
FANCM	ENST00000556250.6	TSL:1	c.4171A>G	p.Ile1391Val	missense	Exon 15 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes

AF:

0.0850

AC:

12925

AN:

152120

Hom.:

720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.0984

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.113

AC:

28015

AN:

248340

AF XY:

0.117

show subpopulations

Gnomad AFR exome

AF:

0.0194

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.106

AC:

152926

AN:

1449338

Hom.:

8998

Cov.:

AF XY:

0.108

AC XY:

78171

AN XY:

721746

show subpopulations

African (AFR)

AF:

0.0172

AC:

572

AN:

33278

American (AMR)

AF:

0.112

AC:

4992

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3549

AN:

25906

East Asian (EAS)

AF:

0.122

AC:

4831

AN:

39486

South Asian (SAS)

AF:

0.184

AC:

15812

AN:

85818

European-Finnish (FIN)

AF:

0.119

AC:

6326

AN:

53178

Middle Eastern (MID)

AF:

0.125

AC:

698

AN:

5574

European-Non Finnish (NFE)

AF:

0.0996

AC:

109706

AN:

1101652

Other (OTH)

AF:

0.108

AC:

6440

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

6027

12054

18081

24108

30135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4084

8168

12252

16336

20420

<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:

0.0849

AC:

12925

AN:

152238

Hom.:

718

Cov.:

AF XY:

0.0868

AC XY:

6457

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0218

AC:

907

AN:

41568

American (AMR)

AF:

0.0987

AC:

1509

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

459

AN:

3472

East Asian (EAS)

AF:

0.119

AC:

615

AN:

5178

South Asian (SAS)

AF:

0.182

AC:

878

AN:

4824

European-Finnish (FIN)

AF:

0.107

AC:

1134

AN:

10592

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

7014

AN:

67996

Other (OTH)

AF:

0.108

AC:

228

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

616

1231

1847

2462

3078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.0964

Hom.:

1800

Bravo

AF:

0.0810

TwinsUK

AF:

0.0922

AC:

342

ALSPAC

AF:

0.0937

AC:

361

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.103

AC:

887

ExAC

AF:

0.111

AC:

13510

Asia WGS

AF:

0.126

AC:

438

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:9

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

Fanconi anemia

Benign:2

Jul 10, 2025

GeneKor MSA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Dec 12, 2018

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.0

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.056

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.17

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.15

REVEL

Benign

0.014

Sift

Benign

0.98

Sift4G

Benign

0.33

Polyphen

0.015

Vest4

0.065

MPC

0.071

ClinPred

0.000013

GERP RS

-1.2

Varity_R

0.032

gMVP

0.055

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over