14-45159080-TTATA-TTA

Position:

• chr14-45159080-TTATA-TTA

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BA1

The NM_020937.4(FANCM):​c.1397-3_1397-2delTA variant causes a splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,415,016 control chromosomes in the GnomAD database, including 8,448 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.091 (764 hom., cov: 30)
  • Exomes 𝑓: 0.11 (7684 hom.)
• Consequence: FANCM NM_020937.4 splice_acceptor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.918

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0299333 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 0 (no position change), new splice context is: aagtttttatatatatatAGctg. 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-TTA-T is Benign according to our data. Variant chr14-45159080-TTA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261381.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4	c.1397-3_1397-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.1397-3_1397-2delTA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13782 AN: 151270 Hom.: 763 Cov.: 30

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.177 AC: 23609 AN: 133184 Hom.: 1461 AF XY: 0.183 AC XY: 13210 AN XY: 72324

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.112 AC: 141719 AN: 1263634 Hom.: 7684 AF XY: 0.115 AC XY: 72393 AN XY: 629880

Gnomad4 AFR exome AF: 0.0401

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.0911 AC: 13789 AN: 151382 Hom.: 764 Cov.: 30 AF XY: 0.0928 AC XY: 6862 AN XY: 73956

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0762 Hom.: 128

Bravo AF: 0.0893

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Premature ovarian failure 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Spermatogenic failure 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs112326758; hg19: chr14-45628283;