12-65308593-A-T

Variant names:

• chr12-65308593-A-T
• rs867897721
• NM_001031679.3:c.14A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001031679.3(MSRB3):​c.14A>T​(p.Asn5Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,970 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N5K) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MSRB3 NM_001031679.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.12
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.14A>T	p.Asn5Ile	missense	Exon 2 of 7	NP_001026849.1	Q8IXL7-2
	MSRB3	NM_001193460.2		c.14A>T	p.Asn5Ile	missense	Exon 3 of 8	NP_001180389.1	Q8IXL7-2
	MSRB3	NM_001193461.2		c.14A>T	p.Asn5Ile	missense	Exon 2 of 7	NP_001180390.1	Q8IXL7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	ENST00000308259.10	TSL:1 MANE Select	c.14A>T	p.Asn5Ile	missense	Exon 2 of 7	ENSP00000312274.6	Q8IXL7-2
	MSRB3	ENST00000535664.5	TSL:1	c.14A>T	p.Asn5Ile	missense	Exon 3 of 8	ENSP00000441650.1	Q8IXL7-2
	MSRB3	ENST00000355192.8	TSL:1	c.98-18233A>T		intron	N/A	ENSP00000347324.3	Q8IXL7-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74238

African (AFR) AF: 0.0000242 AC: 1 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.50	T
PhyloP100		5.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.50		Gain of sheet (P = 0.0149)
MVP		0.76
ClinPred		0.82	D
GERP RS		6.0
Mutation Taster		=59/41	polymorphism

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: rs867897721; hg19: chr12-65702373;