chr12-65278770-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The ENST00000355192.8(MSRB3):ā€‹c.2T>Gā€‹(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 0.0000114 in 1,577,848 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 Likely pathogenic (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

MSRB3
ENST00000355192.8 start_lost

Scores

3
2
11

Clinical Significance

Likely pathogenic criteria provided, single submitter P: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 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in ENST00000355192.8 (MSRB3) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1699605
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-65278770-T-G is Pathogenic according to our data. Variant chr12-65278770-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1324742.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000105
AC:
2
AN:
189636
Hom.:
0
AF XY:
0.0000196
AC XY:
2
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:
0.0000399
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000112
AC:
16
AN:
1425770
Hom.:
0
Cov.:
31
AF XY:
0.0000170
AC XY:
12
AN XY:
705912
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:
0.0000615
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000730
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.00000378
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 74 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 04, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
13
DANN
Benign
0.93
DEOGEN2
Benign
0.24
T;T
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.043
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
D;D;N;N
PROVEAN
Benign
-0.42
N;N
REVEL
Benign
0.26
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.0
B;.
Vest4
0.55
MutPred
0.98
Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);
MVP
0.51
ClinPred
0.18
T
GERP RS
-1.7
Varity_R
0.89
gMVP
0.72

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