Variant rs146539065 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_016955.4(SEPSECS):c.846G>A(p.Leu282=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000651 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SEPSECS
NM_016955.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 7.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-25145092-C-T is Pathogenic according to our data. Variant chr4-25145092-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522806.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}. Variant chr4-25145092-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPSECS	NM_016955.4 linkuse as main transcript	c.846G>A	p.Leu282=	synonymous_variant	7/11	ENST00000382103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPSECS	ENST00000382103.7 linkuse as main transcript	c.846G>A	p.Leu282=	synonymous_variant	7/11	1	NM_016955.4	P1	Q9HD40-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250948

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000836

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 2D

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 12, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Institute for Genomic Medicine, Nationwide Children's Hospital	Oct 01, 2021	This variant was identified in two siblings with PCH type 2D and was compound-heterozygous with an initiator codon variant (c.1A>T) considered to be pathogenic. Although the c.846G>A is a synonymous change, it has been shown to disrupt splicing in experimental work by the UDN (PMID: 31607746). It is extremely rare (AF~0.00004) with no homozygotes reported in public databases including gnomAD and TopMed. We interpret the variant as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 06, 2017	The c.846G>A variant in SEPSECS was shown to result in exon skipping by RNAseq. The variant is present in 6 individuals in gnomAD as heterozygotes. The variant was identifed as a compound heterozygote with c.808dupG that is a frameshift variant. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change affects codon 282 of the SEPSECS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SEPSECS protein. This variant is present in population databases (rs146539065, gnomAD 0.02%). This variant has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 31607746, 35091508). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522806). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 02, 2021

Variant summary: SEPSECS c.846G>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.8e-05 in 250948 control chromosomes. c.846G>A has been reported in the literature in a 2-year-old female with severe hypotonia, global developmental delay with cerebral atrophy, hypomyelination, and central volume loss of the cerebrum who underwent trio genome sequencing and trio RNAseq from blood (Lee_2020). The patient was found to carry a paternal frameshift variant in SEPSECS (c.808dup) while the variant of interest was found on the maternal allele. RNAseq analysis showed the 130-bp exon 7 containing the synonymous variant (p. Leu282=) was skipped in about half of the mRNAs. The novel splice junction that joins exon 6 and exon 8 was detected in 25/695 additional unrelated samples without this variant, but at a much lower ratio compared with our proband and mother, suggesting that exon 7 may be susceptible to low-level skipping. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

6.1

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.42

Position offset: 41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over