10-13319332-C-T

Variant names:

• chr10-13319332-C-T
• rs1833032660
• NM_012247.5:c.989G>A

Variant summary

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

The NM_012247.5(SEPHS1):​c.989G>A​(p.Arg330His) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEPHS1 NM_012247.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPHS1	NM_012247.5	c.989G>A	p.Arg330His	missense_variant	Exon 9 of 9	ENST00000327347.10	NP_036379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPHS1	ENST00000327347.10	c.989G>A	p.Arg330His	missense_variant	Exon 9 of 9	1	NM_012247.5	ENSP00000367893.3
SEPHS1	ENST00000545675.5	c.788G>A	p.Arg263His	missense_variant	Exon 8 of 8	1		ENSP00000441119.2
SEPHS1	ENST00000378614.8	c.776G>A	p.Arg259His	missense_variant	Exon 8 of 8	1		ENSP00000367877.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;.;N
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;.;T
Sift4G	Benign	0.079	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.56
MutPred		0.48		Gain of catalytic residue at Q332 (P = 0.349);.;.;
MVP		0.45
MPC		1.4
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.54
gMVP		0.67

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: rs1833032660; hg19: chr10-13361332; COSMIC: COSV59259297;