16-1943143-C-G

Position:

• chr16-1943143-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000361871.8(MSRB1):​c.14G>C​(p.Ser5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,409,848 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MSRB1 ENST00000361871.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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]

LOC124903625 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22551045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSRB1	NM_016332.4	c.14G>C	p.Ser5Thr	missense_variant	1/4	ENST00000361871.8	NP_057416.1
MSRB1	NM_001382264.1	c.14G>C	p.Ser5Thr	missense_variant	1/4		NP_001369193.1
MSRB1	NM_001382265.1	c.14G>C	p.Ser5Thr	missense_variant	1/3		NP_001369194.1
LOC124903625	XR_007064940.1	n.247C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSRB1	ENST00000361871.8	c.14G>C	p.Ser5Thr	missense_variant	1/4	1	NM_016332.4	ENSP00000355084.3
MSRB1	ENST00000399753.2	c.14G>C	p.Ser5Thr	missense_variant	1/3	3		ENSP00000382657.2
MSRB1	ENST00000564908.1	c.14G>C	p.Ser5Thr	missense_variant	1/5	3		ENSP00000456557.1
MSRB1	ENST00000473663.1	c.-21G>C		upstream_gene_variant		5		ENSP00000457320.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000149 AC: 21 AN: 1409848 Hom.: 0 Cov.: 31 AF XY: 0.0000172 AC XY: 12 AN XY: 696648

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: 0.0000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000870 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.14G>C (p.S5T) alteration is located in exon 1 (coding exon 1) of the MSRB1 gene. This alteration results from a G to C substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.64	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.019	D;.;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.15	B;.;.;.
Vest4		0.35
MutPred		0.61		Loss of disorder (P = 0.0592);Loss of disorder (P = 0.0592);Loss of disorder (P = 0.0592);Loss of disorder (P = 0.0592);
MVP		0.45
MPC		0.14
ClinPred		0.28	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21

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: rs745872195; hg19: chr16-1993144;