Genetic Variant NM_012247.5:c.1111C>T (chr10-13319210-G-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP2PP5_Moderate

The NM_012247.5(SEPHS1):c.1111C>T(p.Arg371Trp) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

SEPHS1
NM_012247.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 8.11

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-13319209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1343385.

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.

PP5

Variant 10-13319210-G-A is Pathogenic according to our data. Variant chr10-13319210-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1343383.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1111C>T	p.Arg371Trp	missense	Exon 9 of 9	NP_036379.2
SEPHS1	NM_001375769.1		c.1105C>T	p.Arg369Trp	missense	Exon 9 of 9	NP_001362698.1
SEPHS1	NM_001195602.2		c.910C>T	p.Arg304Trp	missense	Exon 8 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.1111C>T	p.Arg371Trp	missense	Exon 9 of 9	ENSP00000367893.3	P49903-1
SEPHS1	ENST00000545675.5	TSL:1	c.910C>T	p.Arg304Trp	missense	Exon 8 of 8	ENSP00000441119.2	P49903-3
SEPHS1	ENST00000378614.8	TSL:1	c.898C>T	p.Arg300Trp	missense	Exon 8 of 8	ENSP00000367877.3	P49903-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152170

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

SEPHS1-related disorder (1)

VERVERI-BRADY SYNDROME 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.6

PhyloP100

8.1

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

Sift4G

Benign

0.089

Polyphen

1.0

Vest4

0.79

MutPred

0.53

Loss of MoRF binding (P = 0.0752)

MVP

0.47

MPC

1.2

ClinPred

0.98

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.82

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over