12-65389598-T-C

Variant names:

• chr12-65389598-T-C
• rs10506525
• NM_001031679.3:c.292+20572T>C

Variant summary

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

The NM_001031679.3(MSRB3):​c.292+20572T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 152,026 control chromosomes in the GnomAD database, including 32,021 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 0.65 (32021 hom., cov: 32)
• Consequence: MSRB3 NM_001031679.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 27 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSRB3	NM_001031679.3	c.292+20572T>C		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.292+20572T>C		intron_variant	Intron 5 of 6	1	NM_001031679.3	ENSP00000312274.6

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98406 AN: 151908 Hom.: 31993 Cov.: 32

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.642

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

GnomAD4 genome AF: 0.648 AC: 98472 AN: 152026 Hom.: 32021 Cov.: 32 AF XY: 0.650 AC XY: 48307 AN XY: 74308

African (AFR) AF: 0.649 AC: 26887 AN: 41460

American (AMR) AF: 0.720 AC: 11000 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2076 AN: 3468

East Asian (EAS) AF: 0.567 AC: 2922 AN: 5156

South Asian (SAS) AF: 0.713 AC: 3438 AN: 4820

European-Finnish (FIN) AF: 0.710 AC: 7497 AN: 10558

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42527 AN: 67972

Other (OTH) AF: 0.634 AC: 1340 AN: 2112

Alfa AF: 0.628 Hom.: 134139

Bravo AF: 0.651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.10
DANN	Benign	0.51
PhyloP100		-1.6
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: rs10506525; hg19: chr12-65783378;