rs17408685

Positions:

• chr4-25125687-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016955.4(SEPSECS):​c.1211+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,595,370 control chromosomes in the GnomAD database, including 1,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (203 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1153 hom.)
• Consequence: SEPSECS NM_016955.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001280
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-25125687-T-C is Benign according to our data. Variant chr4-25125687-T-C is described in ClinVar as [Benign]. Clinvar id is 130287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25125687-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEPSECS	NM_016955.4	c.1211+7A>G		splice_region_variant, intron_variant		ENST00000382103.7	NP_058651.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7	c.1211+7A>G		splice_region_variant, intron_variant		1	NM_016955.4	ENSP00000371535	P1

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7006 AN: 152102 Hom.: 205 Cov.: 32

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0612

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0432 AC: 10738 AN: 248298 Hom.: 362 AF XY: 0.0422 AC XY: 5654 AN XY: 134084

Gnomad AFR exome AF: 0.0695

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.0460

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0346 AC: 49969 AN: 1443150 Hom.: 1153 Cov.: 27 AF XY: 0.0349 AC XY: 25077 AN XY: 718994

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0643

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.0465

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0289

Gnomad4 OTH exome AF: 0.0495

GnomAD4 genome AF: 0.0461 AC: 7011 AN: 152220 Hom.: 203 Cov.: 32 AF XY: 0.0457 AC XY: 3405 AN XY: 74430

Gnomad4 AFR AF: 0.0683

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0612

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.0535

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0357 Hom.: 137

Bravo AF: 0.0485

Asia WGS AF: 0.0950 AC: 328 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 2D Benign:3

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.29
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
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: rs17408685; hg19: chr4-25127309; COSMIC: COSV57204715; COSMIC: COSV57204715;