rs760850788

Variant names:

• chr16-1941288-C-A
• NM_016332.4:c.173G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1941288-C-A
• chr16-1941288-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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]

ACMG classification

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
MSRB1	NM_016332.4	c.173G>T	p.Arg58Leu	missense_variant	Exon 2 of 4	ENST00000361871.8	NP_057416.1
MSRB1	NM_001382265.1	c.173G>T	p.Arg58Leu	missense_variant	Exon 2 of 3		NP_001369194.1
MSRB1	NM_001382264.1	c.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
MSRB1	ENST00000361871.8	c.173G>T	p.Arg58Leu	missense_variant	Exon 2 of 4	1	NM_016332.4	ENSP00000355084.3

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

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;