chr12-65278807-C-T

Position:

• chr12-65278807-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The ENST00000355192.8(MSRB3):​c.39C>T​(p.Leu13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,571,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: MSRB3 ENST00000355192.8 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.655

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-65278807-C-T is Benign according to our data. Variant chr12-65278807-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 929972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-65278807-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.655 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00044 (67/152256) while in subpopulation NFE AF= 0.00072 (49/68012). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSRB3	NM_001031679.3	c.-110C>T		5_prime_UTR_variant	1/7	ENST00000308259.10	NP_001026849.1
MSRB3	NM_198080.4	c.39C>T	p.Leu13=	synonymous_variant	1/6		NP_932346.1
MSRB3	NM_001193460.2	c.-274C>T		5_prime_UTR_variant	1/8		NP_001180389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSRB3	ENST00000308259.10	c.-110C>T		5_prime_UTR_variant	1/7	1	NM_001031679.3	ENSP00000312274	P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0000654

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: 0.000720

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000357 AC: 64 AN: 179250 Hom.: 0 AF XY: 0.000387 AC XY: 37 AN XY: 95570

Gnomad AFR exome AF: 0.0000991

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000120

Gnomad NFE exome AF: 0.000702

Gnomad OTH exome AF: 0.000614

GnomAD4 exome AF: 0.000400 AC: 568 AN: 1418898 Hom.: 0 Cov.: 31 AF XY: 0.000402 AC XY: 282 AN XY: 701598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.000100

Gnomad4 NFE exome AF: 0.000495

Gnomad4 OTH exome AF: 0.000221

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74444

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MSRB3: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Leu13Leu in exon 1 of MSRB3: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.14% (19/13160) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150572160). -

MSRB3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs150572160; hg19: chr12-65672587;