8-10054582-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_012331.5(MSRA):c.66G>C(p.Arg22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000505 in 1,584,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. R22W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

MSRA
NM_012331.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.661

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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a mutagenesis_site Impaired subcellular location. (size 0) in uniprot entity MSRA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12303412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRA	NM_012331.5 link	c.66G>C	p.Arg22Ser	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.66G>C	p.Arg22Ser	missense_variant	Exon 1 of 6	1	NM_012331.5	ENSP00000313921.4		Q9UJ68-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD2 exomes

AF:

0.0000134

AC:

AN:

224178

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000235

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000419

AC:

AN:

1431952

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712304

show subpopulations

African (AFR)

AF:

0.000164

AC:

AN:

30496

American (AMR)

AF:

0.0000240

AC:

AN:

41586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25244

East Asian (EAS)

AF:

0.00

AC:

AN:

35552

South Asian (SAS)

AF:

0.00

AC:

AN:

83654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097670

Other (OTH)

AF:

0.00

AC:

AN:

59154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2090

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:

0.0000340

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.66G>C (p.R22S) alteration is located in exon 1 (coding exon 1) of the MSRA gene. This alteration results from a G to C substitution at nucleotide position 66, causing the arginine (R) at amino acid position 22 to be replaced by a serine (S). 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

0.22

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.26

T;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.60

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.

PhyloP100

0.66

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.70

N;N;N

REVEL

Benign

0.059

Sift

Benign

0.081

T;D;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.0030

B;B;.

Vest4

0.48

MutPred

0.39

Loss of methylation at R22 (P = 0.0413);Loss of methylation at R22 (P = 0.0413);Loss of methylation at R22 (P = 0.0413);

MVP

0.19

MPC

0.0015

ClinPred

0.097

GERP RS

2.1

PromoterAI

0.081

Neutral

(source)

Varity_R

0.11

gMVP

0.39

Mutation Taster

=79/21

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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8-10054582-G-C

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