10-13319209-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM2 PM5 PP2 PP5_Moderate BP4

The NM_012247.5(SEPHS1):c.1112G>A(p.Arg371Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,166 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371G) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SEPHS1 NM_012247.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-13319210-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1343384.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SEPHS1
• PP5: Variant 10-13319209-C-T is Pathogenic according to our data. Variant chr10-13319209-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1343385.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25511205).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPHS1	NM_012247.5	c.1112G>A	p.Arg371Gln	missense_variant	9/9	ENST00000327347.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPHS1	ENST00000327347.10	c.1112G>A	p.Arg371Gln	missense_variant	9/9	1	NM_012247.5	P1
SEPHS1	ENST00000545675.5	c.911G>A	p.Arg304Gln	missense_variant	8/8	1
SEPHS1	ENST00000378614.8	c.899G>A	p.Arg300Gln	missense_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.094	T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.21
Sift	Benign	0.082	T;.;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.20	B;.;.
Vest4		0.49
MutPred		0.44		Loss of MoRF binding (P = 0.0268);.;.;
MVP		0.60
MPC		1.3
ClinPred		0.79	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.75

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: rs1833029885; hg19: chr10-13361209; COSMIC: COSV100526011;