rs760850788

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_001382264.1(MSRB1):​c.172+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MSRB1
NM_001382264.1 splice_donor, intron

Scores

2
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26
Variant links:
Genes affected
MSRB1 (HGNC:14133): (methionine sulfoxide reductase B1) The protein encoded by this gene belongs to the methionine-R-sulfoxide reductase B (MsrB) family. Members of this family function as repair enzymes that protect proteins from oxidative stress by catalyzing the reduction of methionine-R-sulfoxides to methionines. This protein is highly expressed in liver and kidney, and is localized to the nucleus and cytosol. It is the only member of the MsrB family that is a selenoprotein, containing a selenocysteine (Sec) residue at its active site. It also has the highest methionine-R-sulfoxide reductase activity compared to other members containing cysteine in place of Sec. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A pseudogene of this locus has been identified on chromosome 19. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.4105263 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 32, new splice context is: aagGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSRB1NM_016332.4 linkc.173G>T p.Arg58Leu missense_variant Exon 2 of 4 ENST00000361871.8 NP_057416.1 Q9NZV6
MSRB1NM_001382265.1 linkc.173G>T p.Arg58Leu missense_variant Exon 2 of 3 NP_001369194.1
MSRB1NM_001382264.1 linkc.172+1G>T splice_donor_variant, intron_variant Intron 2 of 3 NP_001369193.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSRB1ENST00000361871.8 linkc.173G>T p.Arg58Leu missense_variant Exon 2 of 4 1 NM_016332.4 ENSP00000355084.3 Q9NZV6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461666
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
727132
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.050
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T;T;.;.
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.62
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.75
T;T;T;D
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.095
T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.54
N;.;.;.
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.9
N;.;N;N
REVEL
Benign
0.073
Sift
Benign
0.77
T;.;D;T
Sift4G
Benign
0.63
T;T;T;T
Polyphen
0.029
B;.;.;.
Vest4
0.47
MutPred
0.34
Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP
0.39
MPC
0.17
ClinPred
0.26
T
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1991289; API