12-65278770-T-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The ENST00000355192.8(MSRB3):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000951 in 1,577,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000098 ( 0 hom. )
Consequence
MSRB3
ENST00000355192.8 start_lost
ENST00000355192.8 start_lost
Scores
3
2
11
Clinical Significance
Conservation
PhyloP100: 0.559
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 Pathogenic. Variant got 13 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in ENST00000355192.8 (MSRB3) was described as [Likely_pathogenic] in ClinVar as 1324742
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-65278770-T-C is Pathogenic according to our data. Variant chr12-65278770-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1699605.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSRB3 | NM_001031679.3 | c.-147T>C | 5_prime_UTR_variant | 1/7 | ENST00000308259.10 | ||
MSRB3 | NM_198080.4 | c.2T>C | p.Met1? | start_lost | 1/6 | ||
MSRB3 | NM_001193460.2 | c.-311T>C | 5_prime_UTR_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSRB3 | ENST00000308259.10 | c.-147T>C | 5_prime_UTR_variant | 1/7 | 1 | NM_001031679.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000527 AC: 1AN: 189636Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 102108
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GnomAD4 exome AF: 0.00000982 AC: 14AN: 1425814Hom.: 0 Cov.: 31 AF XY: 0.0000113 AC XY: 8AN XY: 705930
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 17, 2022 | This sequence change affects the initiator methionine of the MSRB3 mRNA. The next in-frame methionine is located at codon 128. This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with MSRB3-related conditions. This variant disrupts a region of the MSRB3 protein in which other variant(s) (p.Cys89Gly) have been determined to be pathogenic (PMID: 21185009). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;N;N
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MutPred
Gain of phosphorylation at M1 (P = 0.0084);Gain of phosphorylation at M1 (P = 0.0084);
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at