chr12-65278842-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000355192.8(MSRB3):​c.74C>T​(p.Ala25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,412,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MSRB3
ENST00000355192.8 missense

Scores

1
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.755
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17058602).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSRB3NM_001031679.3 linkuse as main transcriptc.-75C>T 5_prime_UTR_variant 1/7 ENST00000308259.10 NP_001026849.1
MSRB3NM_198080.4 linkuse as main transcriptc.74C>T p.Ala25Val missense_variant 1/6 NP_932346.1
MSRB3NM_001193460.2 linkuse as main transcriptc.-239C>T 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.-75C>T 5_prime_UTR_variant 1/71 NM_001031679.3 ENSP00000312274 P1Q8IXL7-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000354
AC:
5
AN:
1412264
Hom.:
0
Cov.:
31
AF XY:
0.00000573
AC XY:
4
AN XY:
697730
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:
0.00000276
Gnomad4 OTH exome
AF:
0.0000341
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 26, 2022The c.74C>T (p.A25V) alteration is located in exon 1 (coding exon 1) of the MSRB3 gene. This alteration results from a C to T substitution at nucleotide position 74, causing the alanine (A) at amino acid position 25 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.090
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
15
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;T
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.46
T;T
M_CAP
Pathogenic
0.49
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.55
N;.
MutationTaster
Benign
1.0
N;N;N;N
PROVEAN
Benign
0.40
N;N
REVEL
Benign
0.13
Sift
Benign
0.59
T;T
Sift4G
Benign
0.40
T;T
Polyphen
0.0030
B;.
Vest4
0.22
MutPred
0.50
Gain of catalytic residue at S29 (P = 0);Gain of catalytic residue at S29 (P = 0);
MVP
0.35
MPC
0.42
ClinPred
0.18
T
GERP RS
2.7
Varity_R
0.044
gMVP
0.27

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: rs1871819343; hg19: chr12-65672622; API