rs387907088

Variant names:

• chr12-65328584-T-G
• rs387907088
• NM_001031679.3:c.244T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_001031679.3(MSRB3):​c.244T>G​(p.Cys82Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,459,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MSRB3 NM_001031679.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.79
• Publications: 11 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 12-65328584-T-G is Pathogenic according to our data. Variant chr12-65328584-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31055.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRB3	NM_001031679.3	c.244T>G	p.Cys82Gly	missense_variant	Exon 4 of 7	ENST00000308259.10	NP_001026849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRB3	ENST00000308259.10	c.244T>G	p.Cys82Gly	missense_variant	Exon 4 of 7	1	NM_001031679.3	ENSP00000312274.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251248 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

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: 0.0000137 AC: 20 AN: 1459706 Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 18 AN XY: 726380

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110306

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 74 Pathogenic:2

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hearing loss, autosomal recessive Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.92	D;.;D;.;.;.;D;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;.;D;.;D;D;.;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-12	D;D;D;D;D;.;D;.;.;.;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;.;.;.
Polyphen		1.0	D;D;.;D;.;D;.;D;D;D;.
Vest4		0.93
MutPred		0.81		Gain of catalytic residue at K85 (P = 0);.;Gain of catalytic residue at K85 (P = 0);.;.;.;.;.;.;.;.;
MVP		0.85
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0071	Neutral
Varity_R		0.99
gMVP		0.86
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387907088; hg19: chr12-65722364;