10-13336244-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_012247.5(SEPHS1):c.404G>C(p.Arg135Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SEPHS1 NM_012247.5 missense, splice_region
• Scores: Splicing: ADA: 0.8334
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SEPHS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.22115287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPHS1	NM_012247.5	c.404G>C	p.Arg135Thr	missense_variant, splice_region_variant	4/9	ENST00000327347.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPHS1	ENST00000327347.10	c.404G>C	p.Arg135Thr	missense_variant, splice_region_variant	4/9	1	NM_012247.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Jan 29, 2024

The c.404G>C (p.R135T) alteration is located in exon 4 (coding exon 3) of the SEPHS1 gene. This alteration results from a G to C substitution at nucleotide position 404, causing the arginine (R) at amino acid position 135 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Benign	0.098	T;.;.;T;T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.20	T;.;T;T;T
Sift4G	Benign	0.26	T;T;T;.;.
Polyphen		0.0020	B;.;.;.;.
Vest4		0.41
MutPred		0.40		Gain of phosphorylation at R135 (P = 0.062);.;Gain of phosphorylation at R135 (P = 0.062);Gain of phosphorylation at R135 (P = 0.062);.;
MVP		0.18
MPC		1.5
ClinPred		0.69	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.52
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: chr10-13378244;