rs140998495

Positions:

• chr14-45151519-G-A
• chr14-45151519-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020937.4(FANCM):​c.1041G>A​(p.Pro347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,611,722 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (35 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.739

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-45151519-G-A is Benign according to our data. Variant chr14-45151519-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.739 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.003 (457/152244) while in subpopulation AMR AF= 0.0207 (316/15290). AF 95% confidence interval is 0.0188. There are 6 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.1041G>A	p.Pro347=	synonymous_variant	5/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.1041G>A	p.Pro347=	synonymous_variant	5/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152126 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00594 AC: 1490 AN: 250982 Hom.: 25 AF XY: 0.00465 AC XY: 631 AN XY: 135766

Gnomad AFR exome AF: 0.000558

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0162

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00163 AC: 2383 AN: 1459478 Hom.: 35 Cov.: 29 AF XY: 0.00144 AC XY: 1044 AN XY: 726226

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.0316

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0181

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152244 Hom.: 6 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74444

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.00433

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2021	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140998495; hg19: chr14-45620722; COSMIC: COSV99951510; COSMIC: COSV99951510;