Genetic Variant MSRA:c.143-5delT (chr8-10207815-CT-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_012331.5(MSRA):c.143-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,100,422 control chromosomes in the GnomAD database, including 4 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 0.0061 ( 3 hom., cov: 32)

Exomes 𝑓: 0.11 ( 1 hom. )

Consequence

MSRA
NM_012331.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.07

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRA	NM_012331.5 link	c.143-5delT		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.143-17delT		intron_variant	Intron 1 of 5	1	NM_012331.5	ENSP00000313921.4		Q9UJ68-1

Frequencies

GnomAD3 genomes

AF:

0.00607

AC:

878

AN:

144740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00574

Gnomad ASJ

AF:

0.000891

Gnomad EAS

AF:

0.00240

Gnomad SAS

AF:

0.00130

Gnomad FIN

AF:

0.00483

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00711

GnomAD2 exomes

AF:

0.268

AC:

26836

AN:

100002

AF XY:

0.269

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.275

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.112

AC:

107208

AN:

955672

Hom.:

Cov.:

AF XY:

0.115

AC XY:

55007

AN XY:

476538

show subpopulations

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

African (AFR)

AF:

0.133

AC:

2925

AN:

21940

American (AMR)

AF:

0.165

AC:

4911

AN:

29810

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

2515

AN:

17572

East Asian (EAS)

AF:

0.148

AC:

3791

AN:

25554

South Asian (SAS)

AF:

0.149

AC:

8640

AN:

58132

European-Finnish (FIN)

AF:

0.150

AC:

5032

AN:

33598

Middle Eastern (MID)

AF:

0.102

AC:

366

AN:

3588

European-Non Finnish (NFE)

AF:

0.102

AC:

74204

AN:

725758

Other (OTH)

AF:

0.121

AC:

4824

AN:

39720

⚠️ 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: 0.260

Heterozygous variant carriers

13126

26252

39377

52503

65629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00613

AC:

887

AN:

144750

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

419

AN XY:

70340

show subpopulations

African (AFR)

AF:

0.0160

AC:

635

AN:

39722

American (AMR)

AF:

0.00573

AC:

AN:

14478

Ashkenazi Jewish (ASJ)

AF:

0.000891

AC:

AN:

3368

East Asian (EAS)

AF:

0.00241

AC:

AN:

4984

South Asian (SAS)

AF:

0.00131

AC:

AN:

4580

European-Finnish (FIN)

AF:

0.00483

AC:

AN:

8894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

65568

Other (OTH)

AF:

0.00758

AC:

AN:

1980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0616

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=98/2

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr8-10207815-CT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over