rs7142192

chr14-45189212-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020937.4(FANCM):c.5190G>A(p.Gln1730=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,114 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (19 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.477

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=-0.84).
• BP6: Variant 14-45189212-G-A is Benign according to our data. Variant chr14-45189212-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45189212-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.477 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00858 (1307/152262) while in subpopulation AFR AF= 0.0299 (1241/41542). AF 95% confidence interval is 0.0285. There are 17 homozygotes in gnomad4. There are 593 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.5190G>A	p.Gln1730=	synonymous_variant	20/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.5190G>A	p.Gln1730=	synonymous_variant	20/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.00856 AC: 1302 AN: 152144 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00227 AC: 571 AN: 251156 Hom.: 6 AF XY: 0.00147 AC XY: 200 AN XY: 135718

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000967 AC: 1413 AN: 1461852 Hom.: 19 Cov.: 32 AF XY: 0.000831 AC XY: 604 AN XY: 727232

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00858 AC: 1307 AN: 152262 Hom.: 17 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74462

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00415 Hom.: 5

Bravo AF: 0.00955

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 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

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.3
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7142192; hg19: chr14-45658415; COSMIC: COSV104566905; COSMIC: COSV104566905;