rs142333130

chr14-45198735-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_020937.4(FANCM):c.5808C>T(p.Ser1936=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,613,942 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.225

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-45198735-C-T is Benign according to our data. Variant chr14-45198735-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.225 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.5808C>T	p.Ser1936=	synonymous_variant	22/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.5808C>T	p.Ser1936=	synonymous_variant	22/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251334 Hom.: 2 AF XY: 0.000390 AC XY: 53 AN XY: 135838

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000179 AC: 262 AN: 1461746 Hom.: 2 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727180

Gnomad4 AFR exome AF: 0.00574

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74418

Gnomad4 AFR AF: 0.00598

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000867 Hom.: 0

Bravo AF: 0.00192

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2020

- -

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

Jan 19, 2024

- -

Spermatogenic failure 28;C4748170:Premature ovarian failure 15 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 17, 2021

- -

FANCM-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	9.5
Dann	Benign	0.96

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: rs142333130; hg19: chr14-45667938;