4-25152049-C-T

Variant names:

• chr4-25152049-C-T
• rs267607035
• NM_016955.4:c.715G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.94
• Publications: 11 publications found

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

ACMG classification

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

Selected	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
	SEPSECS	NM_001410714.1		c.970G>A	p.Ala324Thr	missense	Exon 7 of 12	NP_001397643.1

Ensembl Transcripts

Selected	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
	SEPSECS	ENST00000358971.7	TSL:1	n.*513G>A		non_coding_transcript_exon	Exon 7 of 12	ENSP00000351857.3
	SEPSECS	ENST00000514585.5	TSL:1	n.*416G>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000421880.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152040 Hom.: 0 Cov.: 32

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: 5 AN: 251078 AF XY: 0.0000221

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: 17 AN: 1404250 Hom.: 0 Cov.: 24 AF XY: 0.0000142 AC XY: 10 AN XY: 702264

African (AFR) AF: 0.00 AC: 0 AN: 32320

American (AMR) AF: 0.0000672 AC: 3 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.000194 AC: 5 AN: 25740

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 84972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1059850

Other (OTH) AF: 0.0000855 AC: 5 AN: 58470

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 2D Pathogenic:5

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Feb 21, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_016955.3(SEPSECS):c.715G>A(A239T) is a missense variant classified as likely pathogenic in the context of pontocerebellar hypoplasia, SEPSECS-related. A239T has been observed in cases with relevant disease (PMID: 20920667, 39825153, 33600046). Relevant functional assessments of this variant are available in the literature (PMID: 20920667, 27576344). A239T has been observed in referenced population frequency databases. In summary, NM_016955.3(SEPSECS):c.715G>A(A239T) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Oct 08, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 30, 2020

Institute of Human Genetics, Cologne University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Feb 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Apr 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the p.(A239T) variant results in a non-functional misfolded protein and therefore results in a loss of enzyme activity (PMID: 27576344, 20920667); Observed in three unrelated patients with a second variant on the opposite allele (in trans) in the published literature (PMID: 20920667, 33600046); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20920667, 31589614, 33600046, 27576344)

Dec 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the SEPSECS protein (p.Ala239Thr). This variant is present in population databases (rs267607035, gnomAD 0.01%). This missense change has been observed in individual(s) with progressive cerebellocerebral atrophy (PMID: 20920667). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 18401). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SEPSECS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SEPSECS function (PMID: 20920667, 27576344). For these reasons, this variant has been classified as Pathogenic.

Pontoneocerebellar hypoplasia Pathogenic:1

Aug 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SEPSECS c.715G>A (p.Ala239Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 252236 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in SEPSECS causing Pontocerebellar Hypoplasia, Type 2D (4.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.715G>A has been reported in the literature in individuals affected with progressive cerebellocerebral atrophy or progressive axonal polyneuropathy (Agamy_2010, Iwama_2016, Keller_2021). These data indicate that the variant is likely to be associated with disease. At least two functional studies report experimental evidence evaluating an impact on protein function and this variant caused complete inactivity of SEPSECS due to it's insolubility and inability to form productive tetramers (Agamy_2010, Puppala_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.83		Loss of stability (P = 0.1598)
MVP		0.96
MPC		0.36
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.80
gMVP		0.86
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607035; hg19: chr4-25153671;