rs34252356

Positions:

• chr14-45185207-TCTTA-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_020937.4(FANCM):​c.4516-5_4516-2delCTTA 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 0.14 in 1,551,594 control chromosomes in the GnomAD database, including 20,026 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5284 hom., cov: 26)
  • Exomes 𝑓: 0.13 (14742 hom.)
• Consequence: FANCM NM_020937.4 splice_acceptor, splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00

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 -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025378233 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.7, offset of 0 (no position change), new splice context is: tgttttctaatttgtcttAGcat. 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 14-45185207-TCTTA-T is Benign according to our data. Variant chr14-45185207-TCTTA-T is described in ClinVar as [Benign]. Clinvar id is 261387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4	c.4516-5_4516-2delCTTA		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.4516-5_4516-2delCTTA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33449 AN: 151814 Hom.: 5247 Cov.: 26

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.161 AC: 39100 AN: 243140 Hom.: 3919 AF XY: 0.156 AC XY: 20512 AN XY: 131516

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.132 AC: 184163 AN: 1399664 Hom.: 14742 AF XY: 0.133 AC XY: 92891 AN XY: 699012

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.221 AC: 33545 AN: 151930 Hom.: 5284 Cov.: 26 AF XY: 0.218 AC XY: 16232 AN XY: 74294

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.213

Alfa AF: 0.167 Hom.: 574

Bravo AF: 0.235

Asia WGS AF: 0.180 AC: 627 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2016	- -
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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2019

This variant is associated with the following publications: (PMID: 33552906) -

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)		0.060		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: rs796584585; hg19: chr14-45654410;