Genetic Variant FANCM:c.1397-3_1397-2dupTA (chr14-45159080-T-TTA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PVS1_ModeratePM2BP6_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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 14-45159080-T-TTA is Benign according to our data. Variant chr14-45159080-T-TTA is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

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

GnomAD4 exome

AF:

0.00346

AC:

4360

AN:

1259136

Hom.:

Cov.:

AF XY:

0.00331

AC XY:

2078

AN XY:

627828

show subpopulations

Gnomad4 AFR exome

AF:

0.00533

Gnomad4 AMR exome

AF:

0.00200

Gnomad4 ASJ exome

AF:

0.00105

Gnomad4 EAS exome

AF:

0.000947

Gnomad4 SAS exome

AF:

0.00339

Gnomad4 FIN exome

AF:

0.000549

Gnomad4 NFE exome

AF:

0.00379

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.000687

AC:

104

AN:

151404

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

AN XY:

73974

show subpopulations

Gnomad4 AFR

AF:

0.00201

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0000965

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000476

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

14-45159080-TTATA-TTATATA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over