chr12-65278778-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198080.4(MSRB3):c.10C>T(p.Arg4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,425,070 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R4R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MSRB3
NM_198080.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.97

Publications

2 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:

ENSG00000298493 (HGNC:):

ENSG00000298493 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10580784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSRB3	NM_001031679.3	MANE Select	c.-139C>T		5_prime_UTR	Exon 1 of 7	NP_001026849.1
MSRB3	NM_198080.4		c.10C>T	p.Arg4Trp	missense	Exon 1 of 6	NP_932346.1
MSRB3	NM_001193460.2		c.-303C>T		5_prime_UTR	Exon 1 of 8	NP_001180389.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSRB3	ENST00000355192.8	TSL:1	c.10C>T	p.Arg4Trp	missense	Exon 1 of 6	ENSP00000347324.3
MSRB3	ENST00000308259.10	TSL:1 MANE Select	c.-139C>T		5_prime_UTR	Exon 1 of 7	ENSP00000312274.6
MSRB3	ENST00000535664.5	TSL:1	c.-303C>T		5_prime_UTR	Exon 1 of 8	ENSP00000441650.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000214

AC:

AN:

186552

AF XY:

0.0000199

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000213

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1425070

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

705456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32576

American (AMR)

AF:

0.00

AC:

AN:

40034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.0000266

AC:

AN:

37642

South Asian (SAS)

AF:

0.0000369

AC:

AN:

81194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094728

Other (OTH)

AF:

0.00

AC:

AN:

58948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000341

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

2.0

PROVEAN

Benign

0.59

REVEL

Benign

0.061

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.016

Polyphen

0.0010

Vest4

0.25

MutPred

0.39

Gain of catalytic residue at P3 (P = 0.0408)

MVP

0.33

MPC

0.53

ClinPred

0.34

GERP RS

2.8

PromoterAI

0.0020

Neutral

(source)

Varity_R

0.13

gMVP

0.39

Mutation Taster

=93/7

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over