chr8-10301625-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012331.5(MSRA):ā€‹c.423C>Gā€‹(p.His141Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,594 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 Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.000050 ( 0 hom. )

Consequence

MSRA
NM_012331.5 missense

Scores

10
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20
Variant links:
Genes affected
MSRA (HGNC:7377): (methionine sulfoxide reductase A) This gene encodes a ubiquitous and highly conserved protein that carries out the enzymatic reduction of methionine sulfoxide to methionine. Human and animal studies have shown the highest levels of expression in kidney and nervous tissue. The protein functions in the repair of oxidatively damaged proteins to restore biological activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSRANM_012331.5 linkuse as main transcriptc.423C>G p.His141Gln missense_variant 4/6 ENST00000317173.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSRAENST00000317173.9 linkuse as main transcriptc.423C>G p.His141Gln missense_variant 4/61 NM_012331.5 P1Q9UJ68-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251350
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000499
AC:
73
AN:
1461478
Hom.:
0
Cov.:
30
AF XY:
0.0000468
AC XY:
34
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000479
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000450
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000725
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2022The c.423C>G (p.H141Q) alteration is located in exon 4 (coding exon 4) of the MSRA gene. This alteration results from a C to G substitution at nucleotide position 423, causing the histidine (H) at amino acid position 141 to be replaced by a glutamine (Q). 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
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.33
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.92
D;.;T;.;.;.
Eigen
Uncertain
0.25
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.81
D
M_CAP
Benign
0.052
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D
MetaSVM
Benign
-0.30
T
MutationAssessor
Pathogenic
4.4
H;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-8.0
D;D;D;D;D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;.;D
Vest4
0.91
MutPred
0.86
Loss of catalytic residue at H141 (P = 0.0483);.;Loss of catalytic residue at H141 (P = 0.0483);.;.;.;
MVP
0.29
MPC
0.0042
ClinPred
1.0
D
GERP RS
2.4
Varity_R
0.90
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs367978405; hg19: chr8-10159135; API