8-10054643-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012331.5(MSRA):c.127C>G(p.Gln43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,571,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q43R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MSRA
NM_012331.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.71

Publications

0 publications found

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]

MSRA links:

MSRA-DT (HGNC:55400): (MSRA divergent transcript)

MSRA-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039508075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRA	NM_012331.5 link	c.127C>G	p.Gln43Glu	missense_variant	Exon 1 of 6	ENST00000317173.9	NP_036463.1	Q9UJ68-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRA	ENST00000317173.9 link	c.127C>G	p.Gln43Glu	missense_variant	Exon 1 of 6	1	NM_012331.5	ENSP00000313921.4		Q9UJ68-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152014

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000237

AC:

AN:

211224

AF XY:

0.00000861

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000683

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000311

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000176

AC:

AN:

1419166

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

705932

show subpopulations

African (AFR)

AF:

0.0000337

AC:

AN:

29640

American (AMR)

AF:

0.0000502

AC:

AN:

39878

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24848

East Asian (EAS)

AF:

0.00

AC:

AN:

33844

South Asian (SAS)

AF:

0.00

AC:

AN:

82384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

1091802

Other (OTH)

AF:

0.00

AC:

AN:

58526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.127C>G (p.Q43E) alteration is located in exon 1 (coding exon 1) of the MSRA gene. This alteration results from a C to G substitution at nucleotide position 127, causing the glutamine (Q) at amino acid position 43 to be replaced by a glutamic acid (E). 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

0.077

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.1

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.14

T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.027

M_CAP

Benign

0.0066

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.86

N;N;.

PhyloP100

-1.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.080

N;N;N

REVEL

Benign

0.0020

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.078

MutPred

0.23

Loss of methylation at K41 (P = 0.0778);Loss of methylation at K41 (P = 0.0778);Loss of methylation at K41 (P = 0.0778);

MVP

0.16

MPC

0.0016

ClinPred

0.027

GERP RS

-3.8

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.068

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(source)

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

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8-10054643-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over