rs34513088

Variant names:

• chr12-65453792-T-C
• rs34513088
• NM_001031679.3:c.357T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_001031679.3(MSRB3):​c.357T>C​(p.Tyr119Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,614,066 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (213 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (184 hom.)
• Consequence: MSRB3 NM_001031679.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.489
• Publications: 1 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 Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.282).
• BP6: Variant 12-65453792-T-C is Benign according to our data. Variant chr12-65453792-T-C is described in ClinVar as Benign. ClinVar VariationId is 44118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031679.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	NM_001031679.3	MANE Select	c.357T>C	p.Tyr119Tyr	synonymous	Exon 6 of 7	NP_001026849.1	Q8IXL7-2
	MSRB3	NM_198080.4		c.378T>C	p.Tyr126Tyr	synonymous	Exon 5 of 6	NP_932346.1	Q8IXL7-1
	MSRB3	NM_001193460.2		c.357T>C	p.Tyr119Tyr	synonymous	Exon 7 of 8	NP_001180389.1	Q8IXL7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	ENST00000308259.10	TSL:1 MANE Select	c.357T>C	p.Tyr119Tyr	synonymous	Exon 6 of 7	ENSP00000312274.6	Q8IXL7-2
	MSRB3	ENST00000355192.8	TSL:1	c.378T>C	p.Tyr126Tyr	synonymous	Exon 5 of 6	ENSP00000347324.3	Q8IXL7-1
	MSRB3	ENST00000535664.5	TSL:1	c.357T>C	p.Tyr119Tyr	synonymous	Exon 7 of 8	ENSP00000441650.1	Q8IXL7-2

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4198 AN: 152098 Hom.: 212 Cov.: 32

Gnomad AFR AF: 0.0970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00732 AC: 1840 AN: 251258 AF XY: 0.00530

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00279 AC: 4084 AN: 1461850 Hom.: 184 Cov.: 31 AF XY: 0.00242 AC XY: 1763 AN XY: 727228

African (AFR) AF: 0.103 AC: 3449 AN: 33476

American (AMR) AF: 0.00454 AC: 203 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111988

Other (OTH) AF: 0.00551 AC: 333 AN: 60396

GnomAD4 genome AF: 0.0276 AC: 4204 AN: 152216 Hom.: 213 Cov.: 32 AF XY: 0.0261 AC XY: 1942 AN XY: 74434

African (AFR) AF: 0.0968 AC: 4018 AN: 41492

American (AMR) AF: 0.00922 AC: 141 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0144 Hom.: 57

Bravo AF: 0.0318

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.063
DANN	Benign	0.20
PhyloP100		-0.49
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34513088; hg19: chr12-65847572;