dbSNP rs267607035: SEPSECS:p.Ala239Pro (chr4-25152049-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_016955.4(SEPSECS):c.715G>C(p.Ala239Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,250 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. A239T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SEPSECS
NM_016955.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Publications

0 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: Broad Center for Mendelian Genomics, PanelApp Australia, G2P, Ambry Genetics, 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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPSECS	NM_016955.4 link	c.715G>C	p.Ala239Pro	missense_variant	Exon 6 of 11	ENST00000382103.7	NP_058651.3	Q9HD40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7 link	c.715G>C	p.Ala239Pro	missense_variant	Exon 6 of 11	1	NM_016955.4	ENSP00000371535.2		Q9HD40-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32320

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25740

East Asian (EAS)

AF:

0.00

AC:

AN:

39240

South Asian (SAS)

AF:

0.00

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:

0.00

AC:

AN:

1059850

Other (OTH)

AF:

0.0000171

AC:

AN:

58470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.1

PhyloP100

2.9

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.94

MutPred

0.85

Loss of stability (P = 0.0659);

MVP

0.98

MPC

0.47

ClinPred

0.99

GERP RS

4.7

Varity_R

0.97

gMVP

0.98

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over