10-13344856-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_012247.5(SEPHS1):c.95A>G(p.Lys32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPHS1 NM_012247.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

Genes affected

SEPHS1 (HGNC:19685): (selenophosphate synthetase 1) This gene encodes an enzyme that synthesizes selenophosphate from selenide and ATP. Selenophosphate is the selenium donor used to synthesize selenocysteine, which is co-translationally incorporated into selenoproteins at in-frame UGA codons. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a site Important for catalytic activity (size 0) in uniprot entity SPS1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SEPHS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPHS1	NM_012247.5	c.95A>G	p.Lys32Arg	missense_variant	2/9	ENST00000327347.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPHS1	ENST00000327347.10	c.95A>G	p.Lys32Arg	missense_variant	2/9	1	NM_012247.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Feb 17, 2022

The c.95A>G (p.K32R) alteration is located in exon 2 (coding exon 1) of the SEPHS1 gene. This alteration results from a A to G substitution at nucleotide position 95, causing the lysine (K) at amino acid position 32 to be replaced by an arginine (R). 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
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.9	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.077	T;T;.
Polyphen		0.99	D;.;.
Vest4		0.87
MutPred		0.45		Loss of methylation at K32 (P = 0.0067);Loss of methylation at K32 (P = 0.0067);Loss of methylation at K32 (P = 0.0067);
MVP		0.84
MPC		1.9
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.57
gMVP		0.98

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: chr10-13386856;