12-65278778-C-G

Variant names:

• chr12-65278778-C-G
• rs182726780
• ENST00000355192.8:c.10C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198080.4(MSRB3):​c.10C>G​(p.Arg4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R4R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSRB3 NM_198080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• 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, 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

ENSG00000298493 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20018905).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198080.4. 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.-139C>G		5_prime_UTR	Exon 1 of 7	NP_001026849.1
	MSRB3	NM_198080.4		c.10C>G	p.Arg4Gly	missense	Exon 1 of 6	NP_932346.1
	MSRB3	NM_001193460.2		c.-303C>G		5_prime_UTR	Exon 1 of 8	NP_001180389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSRB3	ENST00000355192.8	TSL:1	c.10C>G	p.Arg4Gly	missense	Exon 1 of 6	ENSP00000347324.3
	MSRB3	ENST00000308259.10	TSL:1 MANE Select	c.-139C>G		5_prime_UTR	Exon 1 of 7	ENSP00000312274.6
	MSRB3	ENST00000535664.5	TSL:1	c.-303C>G		5_prime_UTR	Exon 1 of 8	ENSP00000441650.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.0
PROVEAN	Benign	0.20	N
REVEL	Benign	0.017
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.085	T
Polyphen		0.16	B
Vest4		0.41
MutPred		0.34		Gain of relative solvent accessibility (P = 0.0275)
MVP		0.41
MPC		0.55
ClinPred		0.41	T
GERP RS		2.8
PromoterAI		-0.023	Neutral
Varity_R		0.13
gMVP		0.34
Mutation Taster		=92/8	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: rs182726780; hg19: chr12-65672558; COSMIC: COSV57596840; COSMIC: COSV57596840;