12-65278794-GC-G

Variant names:

• chr12-65278794-GC-G
• rs574256598
• ENST00000355192.8:c.31delC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PVS1_Strong PM2 BP6 BS1

The NM_198080.4(MSRB3):​c.31delC​(p.Leu11SerfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,571,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: MSRB3 NM_198080.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.30

Genes affected

MSRB3 (HGNC:27375): (methionine sulfoxide reductase B3) The protein encoded by this gene catalyzes the reduction of methionine sulfoxide to methionine. This enzyme acts as a monomer and requires zinc as a cofactor. Several transcript variants encoding two different isoforms have been found for this gene. One of the isoforms localizes to mitochondria while the other localizes to endoplasmic reticula. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.946 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-65278794-GC-G is Benign according to our data. Variant chr12-65278794-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432258.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000637 (97/152208) while in subpopulation AFR AF= 0.00229 (95/41542). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRB3	NM_001031679.3	c.-118delC		5_prime_UTR_variant	Exon 1 of 7	ENST00000308259.10	NP_001026849.1
MSRB3	NM_198080.4	c.31delC	p.Leu11SerfsTer40	frameshift_variant	Exon 1 of 6		NP_932346.1
MSRB3	NM_001193460.2	c.-282delC		5_prime_UTR_variant	Exon 1 of 8		NP_001180389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRB3	ENST00000308259	c.-118delC		5_prime_UTR_variant	Exon 1 of 7	1	NM_001031679.3	ENSP00000312274.6

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000151 AC: 27 AN: 178768 Hom.: 0 AF XY: 0.0000836 AC XY: 8 AN XY: 95712

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.0000365

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: 0.0000135

Gnomad OTH exome AF: 0.000412

GnomAD4 exome AF: 0.0000634 AC: 90 AN: 1418948 Hom.: 0 Cov.: 31 AF XY: 0.0000499 AC XY: 35 AN XY: 701790

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.0000259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000851

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74412

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000729

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2017	The c.31delC variant in the MSRB3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.31delC variant causes a frameshift starting with codon Leucine 11, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Leu11SerfsX40. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.31delC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.31delC as a variant of uncertain significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs574256598; hg19: chr12-65672574;