10-13329705-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_012247.5(SEPHS1):c.644T>G(p.Leu215Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L215Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SEPHS1
NM_012247.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.31

Publications

0 publications found

Variant links:

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]

SEPHS1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, PanelApp Australia

SEPHS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.2396 (above the threshold of 3.09). Trascript score misZ: 4.1 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012247.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEPHS1	NM_012247.5	MANE Select	c.644T>G	p.Leu215Arg	missense	Exon 6 of 9	NP_036379.2
SEPHS1	NM_001375769.1		c.644T>G	p.Leu215Arg	missense	Exon 6 of 9	NP_001362698.1
SEPHS1	NM_001195602.2		c.443T>G	p.Leu148Arg	missense	Exon 5 of 8	NP_001182531.1	P49903-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEPHS1	ENST00000327347.10	TSL:1 MANE Select	c.644T>G	p.Leu215Arg	missense	Exon 6 of 9	ENSP00000367893.3	P49903-1
SEPHS1	ENST00000545675.5	TSL:1	c.443T>G	p.Leu148Arg	missense	Exon 5 of 8	ENSP00000441119.2	P49903-3
SEPHS1	ENST00000378614.8	TSL:1	c.644T>G	p.Leu215Arg	missense	Exon 6 of 8	ENSP00000367877.3	P49903-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1451386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720798

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

42948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25802

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.0000239

AC:

AN:

83602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107410

Other (OTH)

AF:

0.00

AC:

AN:

60046

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.86

MutationAssessor

Pathogenic

3.0

PhyloP100

9.3

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.50

Vest4

0.86

MutPred

0.74

Gain of MoRF binding (P = 0.009)

MVP

0.46

MPC

2.4

ClinPred

1.0

GERP RS

5.4

Varity_R

0.88

gMVP

0.99

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over