chr12-65278770-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5

The ENST00000355192.8(MSRB3):ā€‹c.2T>Cā€‹(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: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000098 ( 0 hom. )

Consequence

MSRB3
ENST00000355192.8 start_lost

Scores

3
2
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.559
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 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: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSRB3NM_001031679.3 linkuse as main transcriptc.-147T>C 5_prime_UTR_variant 1/7 ENST00000308259.10 NP_001026849.1
MSRB3NM_198080.4 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/6 NP_932346.1
MSRB3NM_001193460.2 linkuse as main transcriptc.-311T>C 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.-147T>C 5_prime_UTR_variant 1/71 NM_001031679.3 ENSP00000312274 P1Q8IXL7-2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.00000527
AC:
1
AN:
189636
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
102108
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000982
AC:
14
AN:
1425814
Hom.:
0
Cov.:
31
AF XY:
0.0000113
AC XY:
8
AN XY:
705930
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000128
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
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:
0.00
Bravo
AF:
0.00000378

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 17, 2022This 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 submitterclinical testingGeneDxFeb 01, 2022Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.024
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
14
DANN
Benign
0.90
DEOGEN2
Benign
0.23
T;T
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.015
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
D;D;N;N
PROVEAN
Benign
-0.30
N;N
REVEL
Benign
0.20
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.013
B;.
Vest4
0.59
MutPred
0.94
Gain of phosphorylation at M1 (P = 0.0084);Gain of phosphorylation at M1 (P = 0.0084);
MVP
0.48
ClinPred
0.17
T
GERP RS
-1.7
Varity_R
0.72
gMVP
0.57

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: rs949229098; hg19: chr12-65672550; API