12-65448478-A-G

Variant names:

• chr12-65448478-A-G
• rs1494508
• NM_001031679.3:c.293-5250A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001031679.3(MSRB3):​c.293-5250A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 151,948 control chromosomes in the GnomAD database, including 21,204 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 0.52 (21204 hom., cov: 31)
• Consequence: MSRB3 NM_001031679.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.222
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRB3	NM_001031679.3	c.293-5250A>G		intron_variant	Intron 5 of 6	ENST00000308259.10	NP_001026849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSRB3	ENST00000308259.10	c.293-5250A>G		intron_variant	Intron 5 of 6	1	NM_001031679.3	ENSP00000312274.6

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78681 AN: 151830 Hom.: 21185 Cov.: 31

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.516

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

GnomAD4 genome AF: 0.518 AC: 78720 AN: 151948 Hom.: 21204 Cov.: 31 AF XY: 0.514 AC XY: 38159 AN XY: 74250

African (AFR) AF: 0.369 AC: 15285 AN: 41432

American (AMR) AF: 0.527 AC: 8045 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2017 AN: 3470

East Asian (EAS) AF: 0.438 AC: 2256 AN: 5156

South Asian (SAS) AF: 0.430 AC: 2069 AN: 4816

European-Finnish (FIN) AF: 0.521 AC: 5492 AN: 10546

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41823 AN: 67948

Other (OTH) AF: 0.522 AC: 1099 AN: 2106

Alfa AF: 0.561 Hom.: 22821

Bravo AF: 0.512

Asia WGS AF: 0.443 AC: 1542 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.7
DANN	Benign	0.44
PhyloP100		0.22
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: rs1494508; hg19: chr12-65842258;