dbSNP rs1344945: MSRB3:c.-52+2983T>C (chr12-65281848-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001031679.3(MSRB3):c.-52+2983T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 152,074 control chromosomes in the GnomAD database, including 6,559 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6559 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

MSRB3
NM_001031679.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.349

Publications

8 publications found

Variant links:

Genes affected

MSRB3 (HGNC:27375): (methionine sulfoxide reductase B3) The protein encoded by this gene catalyzes the reduction of methionine sulfoxide to methionine. This enzyme acts as a monomer and requires zinc as a cofactor. Several transcript variants encoding two different isoforms have been found for this gene. One of the isoforms localizes to mitochondria while the other localizes to endoplasmic reticula. [provided by RefSeq, Jul 2010]

MSRB3 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 74
Inheritance: AR, Unknown Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MSRB3 links:

ENSG00000250280 (HGNC:):

ENSG00000250280 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRB3	NM_001031679.3 link	c.-52+2983T>C		intron_variant	Intron 1 of 6	ENST00000308259.10	NP_001026849.1	Q8IXL7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRB3	ENST00000308259.10 link	c.-52+2983T>C		intron_variant	Intron 1 of 6	1	NM_001031679.3	ENSP00000312274.6		Q8IXL7-2

Frequencies

GnomAD3 genomes

AF:

0.292

AC:

44376

AN:

151954

Hom.:

6544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.233

Gnomad AMR

AF:

0.380

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.302

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.300

Gnomad OTH

AF:

0.257

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.292

AC:

44413

AN:

152072

Hom.:

6559

Cov.:

AF XY:

0.292

AC XY:

21728

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.262

AC:

10882

AN:

41492

American (AMR)

AF:

0.380

AC:

5798

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

730

AN:

3472

East Asian (EAS)

AF:

0.232

AC:

1199

AN:

5160

South Asian (SAS)

AF:

0.302

AC:

1456

AN:

4824

European-Finnish (FIN)

AF:

0.297

AC:

3138

AN:

10572

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.300

AC:

20375

AN:

67972

Other (OTH)

AF:

0.264

AC:

558

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1631

3262

4894

6525

8156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.295

Hom.:

5454

Bravo

AF:

0.295

Asia WGS

AF:

0.287

AC:

999

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

4.3

(source)

DANN

Benign

0.77

PhyloP100

-0.35

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over