rs8018014

chr14-45200002-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020937.4(FANCM):c.6141T>C(p.Asp2047=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,606,780 control chromosomes in the GnomAD database, including 396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (133 hom., cov: 32)
  • Exomes 𝑓: 0.015 (263 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.614

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-45200002-T-C is Benign according to our data. Variant chr14-45200002-T-C is described in ClinVar as [Benign]. Clinvar id is 261392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45200002-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.614 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.6141T>C	p.Asp2047=	synonymous_variant	23/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.6141T>C	p.Asp2047=	synonymous_variant	23/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4323 AN: 152180 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0139 AC: 3497 AN: 251028 Hom.: 74 AF XY: 0.0127 AC XY: 1720 AN XY: 135720

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00383

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0155 AC: 22513 AN: 1454482 Hom.: 263 Cov.: 28 AF XY: 0.0149 AC XY: 10818 AN XY: 724026

Gnomad4 AFR exome AF: 0.0721

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00418

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0285 AC: 4335 AN: 152298 Hom.: 133 Cov.: 32 AF XY: 0.0264 AC XY: 1963 AN XY: 74478

Gnomad4 AFR AF: 0.0716

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0178 Hom.: 54

Bravo AF: 0.0308

Asia WGS AF: 0.00839 AC: 29 AN: 3472

EpiCase AF: 0.0133

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Premature ovarian failure 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.79
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8018014; hg19: chr14-45669205; COSMIC: COSV57499820; COSMIC: COSV57499820;