ENST00000355192.8:c.27C>A

Variant names:

• chr12-65278795-C-A
• rs373497233
• ENST00000355192.8:c.27C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP7

The ENST00000355192.8(MSRB3):​c.27C>A​(p.Arg9Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,316 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MSRB3 ENST00000355192.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 0 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

ENSG00000298493 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355192.8. 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.-122C>A		5_prime_UTR	Exon 1 of 7	NP_001026849.1	Q8IXL7-2
	MSRB3	NM_198080.4		c.27C>A	p.Arg9Arg	synonymous	Exon 1 of 6	NP_932346.1	Q8IXL7-1
	MSRB3	NM_001193460.2		c.-286C>A		5_prime_UTR	Exon 1 of 8	NP_001180389.1	Q8IXL7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	ENST00000355192.8	TSL:1	c.27C>A	p.Arg9Arg	synonymous	Exon 1 of 6	ENSP00000347324.3	Q8IXL7-1
	MSRB3	ENST00000308259.10	TSL:1 MANE Select	c.-122C>A		5_prime_UTR	Exon 1 of 7	ENSP00000312274.6	Q8IXL7-2
	MSRB3	ENST00000535664.5	TSL:1	c.-286C>A		5_prime_UTR	Exon 1 of 8	ENSP00000441650.1	Q8IXL7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419316 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 702042

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

African (AFR) AF: 0.00 AC: 0 AN: 32218

American (AMR) AF: 0.00 AC: 0 AN: 38634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37346

South Asian (SAS) AF: 0.00 AC: 0 AN: 80740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091144

Other (OTH) AF: 0.00 AC: 0 AN: 58788

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		1.3
PromoterAI		0.14	Neutral

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: rs373497233; hg19: chr12-65672575;