14-45159080-TTATA-TTATATA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_ModerateBP6_Very_StrongBS1

The NM_020937.4(FANCM):c.1397-3_1397-2dupTA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,410,540 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0035 ( 1 hom. )

Consequence

FANCM
NM_020937.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.244

Publications

4 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 -10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.030095981 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 0 (no position change), new splice context is: ttttatatatatatatatAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 14-45159080-T-TTA is Benign according to our data. Variant chr14-45159080-T-TTA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1219560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000687 (104/151404) while in subpopulation SAS AF = 0.00208 (10/4810). AF 95% confidence interval is 0.00166. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.1397-3_1397-2dupTA		splice_acceptor_variant, intron_variant	Intron 8 of 22	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.1397-16_1397-15insTA		intron_variant	Intron 8 of 22	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.000687

AC:

104

AN:

151292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.0000965

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.00226

AC:

301

AN:

133184

AF XY:

0.00207

show subpopulations

Gnomad AFR exome

AF:

0.00491

Gnomad AMR exome

AF:

0.00371

Gnomad ASJ exome

AF:

0.000978

Gnomad EAS exome

AF:

0.00257

Gnomad FIN exome

AF:

0.000413

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00346

AC:

4360

AN:

1259136

Hom.:

Cov.:

AF XY:

0.00331

AC XY:

2078

AN XY:

627828

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00533

AC:

146

AN:

27368

American (AMR)

AF:

0.00200

AC:

AN:

34974

Ashkenazi Jewish (ASJ)

AF:

0.00105

AC:

AN:

22926

East Asian (EAS)

AF:

0.000947

AC:

AN:

33792

South Asian (SAS)

AF:

0.00339

AC:

239

AN:

70480

European-Finnish (FIN)

AF:

0.000549

AC:

AN:

47380

Middle Eastern (MID)

AF:

0.00257

AC:

AN:

4286

European-Non Finnish (NFE)

AF:

0.00379

AC:

3658

AN:

965788

Other (OTH)

AF:

0.00295

AC:

154

AN:

52142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

613

1226

1839

2452

3065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.000687

AC:

104

AN:

151404

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

AN XY:

73974

show subpopulations

African (AFR)

AF:

0.00201

AC:

AN:

41366

American (AMR)

AF:

0.0000660

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000965

AC:

AN:

10368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67776

Other (OTH)

AF:

0.000476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00544

Hom.:

128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 10, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32338768) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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