12-65368278-G-C

Variant names:

• chr12-65368278-G-C
• rs12229918
• NM_001031679.3:c.264-720G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001031679.3(MSRB3):​c.264-720G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,132 control chromosomes in the GnomAD database, including 6,227 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 0.26 (6227 hom., cov: 32)
• Consequence: MSRB3 NM_001031679.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• Publications: 16 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	NM_001031679.3	MANE Select	c.264-720G>C		intron	N/A	NP_001026849.1
	MSRB3	NM_198080.4		c.285-720G>C		intron	N/A	NP_932346.1
	MSRB3	NM_001193460.2		c.264-720G>C		intron	N/A	NP_001180389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	ENST00000308259.10	TSL:1 MANE Select	c.264-720G>C		intron	N/A	ENSP00000312274.6
	MSRB3	ENST00000355192.8	TSL:1	c.285-720G>C		intron	N/A	ENSP00000347324.3
	MSRB3	ENST00000535664.5	TSL:1	c.264-720G>C		intron	N/A	ENSP00000441650.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39007 AN: 152014 Hom.: 6228 Cov.: 32

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.287

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 39001 AN: 152132 Hom.: 6227 Cov.: 32 AF XY: 0.255 AC XY: 18966 AN XY: 74384

African (AFR) AF: 0.0678 AC: 2815 AN: 41532

American (AMR) AF: 0.229 AC: 3503 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1320 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1983 AN: 5178

South Asian (SAS) AF: 0.251 AC: 1211 AN: 4820

European-Finnish (FIN) AF: 0.256 AC: 2706 AN: 10574

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24448 AN: 67968

Other (OTH) AF: 0.288 AC: 608 AN: 2110

Alfa AF: 0.188 Hom.: 465

Bravo AF: 0.248

Asia WGS AF: 0.302 AC: 1050 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.67
PhyloP100		2.3
Mutation Taster		=100/0	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: rs12229918; hg19: chr12-65762058;