Genetic Variant NM_012247.5:c.1111C>G (chr10-13319210-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM2PM5PP2PP5_ModerateBP4

The NM_012247.5(SEPHS1):c.1111C>G(p.Arg371Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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: not found (cov: 33)

Consequence

SEPHS1
NM_012247.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

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 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 chr10-13319209-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-C is Pathogenic according to our data. Variant chr10-13319210-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1343384.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.28816587). . Strength limited to SUPPORTING due to the PP5.

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>G	p.Arg371Gly	missense	Exon 9 of 9	NP_036379.2
SEPHS1	NM_001375769.1		c.1105C>G	p.Arg369Gly	missense	Exon 9 of 9	NP_001362698.1
SEPHS1	NM_001195602.2		c.910C>G	p.Arg304Gly	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>G	p.Arg371Gly	missense	Exon 9 of 9	ENSP00000367893.3	P49903-1
SEPHS1	ENST00000545675.5	TSL:1	c.910C>G	p.Arg304Gly	missense	Exon 8 of 8	ENSP00000441119.2	P49903-3
SEPHS1	ENST00000378614.8	TSL:1	c.898C>G	p.Arg300Gly	missense	Exon 8 of 8	ENSP00000367877.3	P49903-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

VERVERI-BRADY SYNDROME 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0060

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

PhyloP100

8.1

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.39

Sift

Uncertain

0.0040

Sift4G

Benign

0.072

Polyphen

0.012

Vest4

0.56

MutPred

0.49

Loss of MoRF binding (P = 0.0199)

MVP

0.54

MPC

1.4

ClinPred

0.95

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.88

Mutation Taster

=23/77

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