NM_020937.4:c.4516-5_4516-2delCTTA

Variant names:

• chr14-45185207-TCTTA-T
• rs796584585
• NM_020937.4:c.4516-5_4516-2delCTTA

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025540914 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 VariationId 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 rank	MANE	Protein	UniProt
FANCM	NM_020937.4	c.4516-5_4516-2delCTTA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 17 of 22	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.4516-9_4516-6delCTTA		splice_region_variant, intron_variant	Intron 17 of 22	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

GnomAD2 exomes AF: 0.161 AC: 39100 AN: 243140 AF XY: 0.156

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 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

African (AFR) AF: 0.451 AC: 14160 AN: 31406

American (AMR) AF: 0.178 AC: 7822 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3712 AN: 25550

East Asian (EAS) AF: 0.139 AC: 5444 AN: 39134

South Asian (SAS) AF: 0.201 AC: 16773 AN: 83414

European-Finnish (FIN) AF: 0.125 AC: 6630 AN: 52998

Middle Eastern (MID) AF: 0.168 AC: 936 AN: 5564

European-Non Finnish (NFE) AF: 0.113 AC: 119911 AN: 1059552

Other (OTH) AF: 0.151 AC: 8775 AN: 58026

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

African (AFR) AF: 0.451 AC: 18645 AN: 41318

American (AMR) AF: 0.179 AC: 2736 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3470

East Asian (EAS) AF: 0.135 AC: 700 AN: 5182

South Asian (SAS) AF: 0.201 AC: 970 AN: 4818

European-Finnish (FIN) AF: 0.111 AC: 1173 AN: 10572

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.120 AC: 8163 AN: 67992

Other (OTH) AF: 0.213 AC: 449 AN: 2108

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

Dec 05, 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:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs796584585; hg19: chr14-45654410;