rs267607035

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_016955.4(SEPSECS):c.715G>A(p.Ala239Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,556,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SEPSECS
NM_016955.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.94

Publications

11 publications found

Variant links:

Genes affected

SEPSECS (HGNC:30605): (Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase) The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).[provided by RefSeq, Mar 2011]

SEPSECS Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Broad Center for Mendelian Genomics, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
progressive cerebello-cerebral atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SEPSECS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 4-25152049-C-T is Pathogenic according to our data. Variant chr4-25152049-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	NM_016955.4	MANE Select	c.715G>A	p.Ala239Thr	missense	Exon 6 of 11	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.970G>A	p.Ala324Thr	missense	Exon 7 of 12	NP_001397643.1	A0A7P0TA23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEPSECS	ENST00000382103.7	TSL:1 MANE Select	c.715G>A	p.Ala239Thr	missense	Exon 6 of 11	ENSP00000371535.2	Q9HD40-1
SEPSECS	ENST00000358971.7	TSL:1	n.*513G>A		non_coding_transcript_exon	Exon 7 of 12	ENSP00000351857.3	J3KP25
SEPSECS	ENST00000514585.5	TSL:1	n.*416G>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000421880.1	Q9HD40-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

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

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251078

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1404250

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

702264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32320

American (AMR)

AF:

0.0000672

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.000194

AC:

AN:

25740

East Asian (EAS)

AF:

0.00

AC:

AN:

39240

South Asian (SAS)

AF:

0.0000235

AC:

AN:

84972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1059850

Other (OTH)

AF:

0.0000855

AC:

AN:

58470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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

AF:

0.0000132

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pontocerebellar hypoplasia type 2D (5)

not provided (2)

Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.56

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

3.1

PhyloP100

2.9

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Benign

0.062

Polyphen

0.99

Vest4

0.90

MutPred

0.83

Loss of stability (P = 0.1598)

MVP

0.96

MPC

0.36

ClinPred

0.94

GERP RS

4.7

Varity_R

0.80

gMVP

0.86

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: 13

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over