12-65278794-GC-G
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PVS1_StrongPM2BP6BS1
The ENST00000355192.8(MSRB3):c.31del(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). Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000063 ( 0 hom. )
Consequence
MSRB3
ENST00000355192.8 frameshift
ENST00000355192.8 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 0.953 CDS is truncated, and there are 3 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: {Likely_benign=2, Uncertain_significance=1}.
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/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| MSRB3 | NM_001031679.3 | c.-118del | 5_prime_UTR_variant | 1/7 | ENST00000308259.10 | ||
| MSRB3 | NM_198080.4 | c.31del | p.Leu11SerfsTer40 | frameshift_variant | 1/6 | ||
| MSRB3 | NM_001193460.2 | c.-282del | 5_prime_UTR_variant | 1/8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MSRB3 | ENST00000308259.10 | c.-118del | 5_prime_UTR_variant | 1/7 | 1 | NM_001031679.3 | P1 |
Frequencies
GnomAD3 genomes 0.000638 AC: 97AN: 152090Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000151 AC: 27AN: 178768Hom.: 0 AF XY: 0.0000836 AC XY: 8AN XY: 95712
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GnomAD4 exome AF: 0.0000634 AC: 90AN: 1418948Hom.: 0 Cov.: 31 AF XY: 0.0000499 AC XY: 35AN XY: 701790
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GnomAD4 genome 0.000637 AC: 97AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74412
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | - - |
| 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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at