chr12-65278794-GC-G

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.30
Variant links:
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]

Genome browser will be placed here

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 Protein UniProt
MSRB3NM_001031679.3 linkuse as main transcriptc.-118del 5_prime_UTR_variant 1/7 ENST00000308259.10 NP_001026849.1
MSRB3NM_198080.4 linkuse as main transcriptc.31del p.Leu11SerfsTer40 frameshift_variant 1/6 NP_932346.1
MSRB3NM_001193460.2 linkuse as main transcriptc.-282del 5_prime_UTR_variant 1/8 NP_001180389.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSRB3ENST00000308259.10 linkuse as main transcriptc.-118del 5_prime_UTR_variant 1/71 NM_001031679.3 ENSP00000312274 P1Q8IXL7-2

Frequencies

GnomAD3 genomes
AF:
0.000638
AC:
97
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 05, 2017The 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 submitterclinical testingEurofins Ntd Llc (ga)May 04, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs574256598; hg19: chr12-65672574; API