Genetic Variant NM_012331.5:c.143-5dupT (chr8-10207815-C-CT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_012331.5(MSRA):c.143-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,050,688 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.17 ( 1 hom. )

Consequence

MSRA
NM_012331.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.07

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRA	NM_012331.5 link	c.143-5dupT		splice_region_variant, intron_variant	Intron 1 of 5	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.143-5dupT		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_012331.5	ENSP00000313921.4		Q9UJ68-1

Frequencies

GnomAD3 genomes

AF:

0.00527

AC:

764

AN:

144850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.00304

Gnomad ASJ

AF:

0.00684

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.00109

Gnomad FIN

AF:

0.00672

Gnomad MID

AF:

0.00338

Gnomad NFE

AF:

0.00722

Gnomad OTH

AF:

0.000506

GnomAD2 exomes

AF:

0.181

AC:

18103

AN:

100002

AF XY:

0.182

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.169

AC:

153476

AN:

905826

Hom.:

Cov.:

AF XY:

0.167

AC XY:

75864

AN XY:

453928

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.157

AC:

3261

AN:

20834

American (AMR)

AF:

0.130

AC:

3953

AN:

30414

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

2791

AN:

17340

East Asian (EAS)

AF:

0.146

AC:

3800

AN:

25972

South Asian (SAS)

AF:

0.156

AC:

9143

AN:

58632

European-Finnish (FIN)

AF:

0.129

AC:

4471

AN:

34782

Middle Eastern (MID)

AF:

0.120

AC:

418

AN:

3496

European-Non Finnish (NFE)

AF:

0.176

AC:

119307

AN:

676206

Other (OTH)

AF:

0.166

AC:

6332

AN:

38150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.267

Heterozygous variant carriers

17846

35692

53538

71384

89230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00529

AC:

767

AN:

144862

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

361

AN XY:

70398

show subpopulations

African (AFR)

AF:

0.00395

AC:

157

AN:

39734

American (AMR)

AF:

0.00303

AC:

AN:

14498

Ashkenazi Jewish (ASJ)

AF:

0.00684

AC:

AN:

3364

East Asian (EAS)

AF:

0.000401

AC:

AN:

4984

South Asian (SAS)

AF:

0.00109

AC:

AN:

4580

European-Finnish (FIN)

AF:

0.00672

AC:

AN:

8924

Middle Eastern (MID)

AF:

0.00368

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00721

AC:

473

AN:

65614

Other (OTH)

AF:

0.000503

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0532

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=100/0

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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NM_012331.5:c.143-5dupT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over