rs61747281

Positions:

• chr4-25151984-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_016955.4(SEPSECS):​c.780A>G​(p.Ser260Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,591,588 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: SEPSECS NM_016955.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0450

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 4-25151984-T-C is Benign according to our data. Variant chr4-25151984-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130286.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.045 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEPSECS	NM_016955.4	c.780A>G	p.Ser260Ser	synonymous_variant	6/11	ENST00000382103.7	NP_058651.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7	c.780A>G	p.Ser260Ser	synonymous_variant	6/11	1	NM_016955.4	ENSP00000371535.2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000983 AC: 247 AN: 251254 Hom.: 0 AF XY: 0.000987 AC XY: 134 AN XY: 135816

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00158 AC: 2274 AN: 1439324 Hom.: 1 Cov.: 26 AF XY: 0.00152 AC XY: 1093 AN XY: 717548

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.000988

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00111 AC XY: 83 AN XY: 74450

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00205

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00112

EpiCase AF: 0.00180

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pontocerebellar hypoplasia type 2D Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.9
DANN	Benign	0.75

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

LitVar

Other links and lift over

dbSNP: rs61747281; hg19: chr4-25153606;