rs773876739

Positions:

• chr4-25123971-T-A
• chr4-25123971-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_016955.4(SEPSECS):​c.1466A>T​(p.Asp489Val) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPSECS NM_016955.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.714

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-25123971-T-A is Pathogenic according to our data. Variant chr4-25123971-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190145.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21617785). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPSECS	NM_016955.4	c.1466A>T	p.Asp489Val	missense_variant	11/11	ENST00000382103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPSECS	ENST00000382103.7	c.1466A>T	p.Asp489Val	missense_variant	11/11	1	NM_016955.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pontocerebellar hypoplasia type 2D Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 03, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31130284, 25044680, 29709707) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.048	D
Polyphen		0.43	B
Vest4		0.45
MutPred		0.30		Loss of disorder (P = 0.0143);
MVP		0.96
MPC		0.12
ClinPred		0.22	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs773876739; hg19: chr4-25125593;