12-65278799-C-T

Position:

chr12-65278799-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000355192.8(MSRB3):c.31C>T(p.Leu11Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,571,756 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L11I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

MSRB3
ENST00000355192.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.268

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036703944).

BP6

Variant 12-65278799-C-T is Benign according to our data. Variant chr12-65278799-C-T is described in ClinVar as [Benign]. Clinvar id is 667049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000289 (44/152240) while in subpopulation EAS AF= 0.0074 (38/5134). AF 95% confidence interval is 0.00554. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MSRB3	NM_001031679.3 linkuse as main transcript	c.-118C>T		5_prime_UTR_variant	1/7	ENST00000308259.10
MSRB3	NM_198080.4 linkuse as main transcript	c.31C>T	p.Leu11Phe	missense_variant	1/6
MSRB3	NM_001193460.2 linkuse as main transcript	c.-282C>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSRB3	ENST00000308259.10 linkuse as main transcript	c.-118C>T		5_prime_UTR_variant	1/7	1	NM_001031679.3	P1	Q8IXL7-2

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00738

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000638

AC:

115

AN:

180374

Hom.:

AF XY:

0.000571

AC XY:

AN XY:

96396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00764

Gnomad SAS exome

AF:

0.000247

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.000268

AC:

380

AN:

1419516

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

195

AN XY:

702048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00894

Gnomad4 SAS exome

AF:

0.0000743

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000165

Gnomad4 OTH exome

AF:

0.000374

GnomAD4 genome

AF:

0.000289

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00740

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.000238

ExAC

AF:

0.000555

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Leu11Phe in exon 1 of MSRB3: This variant is not expected to have clinical sig nificance because it has been identified in 1.85% (31/1672) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200778091). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

N;N;N;N

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.095

Sift

Benign

0.17

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0

B;.

Vest4

0.12

MVP

0.52

MPC

0.46

ClinPred

0.031

GERP RS

-0.90

Varity_R

0.051

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over