rs4787645

Variant names:

• chr16-30446029-C-T
• rs4787645
• NM_012248.4:c.-302G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012248.4(SEPHS2):​c.-302G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 313,606 control chromosomes in the GnomAD database, including 25,259 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (10245 hom., cov: 31)
  • Exomes 𝑓: 0.40 (15014 hom.)
• Consequence: SEPHS2 NM_012248.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240

Genes affected

SEPHS2 (HGNC:19686): (selenophosphate synthetase 2) This gene encodes an enzyme that catalyzes the production of monoselenophosphate (MSP) from selenide and ATP. MSP is the selenium donor required for synthesis of selenocysteine (Sec), which is co-translationally incorporated into selenoproteins at in-frame UGA codons that normally signal translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. This protein is itself a selenoprotein containing a Sec residue at its active site, suggesting the existence of an autoregulatory mechanism. It is preferentially expressed in tissues implicated in the synthesis of selenoproteins and in sites of blood cell development. A pseudogene for this locus has been identified on chromosome 5. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPHS2	NM_012248.4	c.-302G>A		upstream_gene_variant		ENST00000478753.5	NP_036380.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPHS2	ENST00000478753.5	c.-302G>A		upstream_gene_variant		6	NM_012248.4	ENSP00000418669.3

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47964 AN: 151652 Hom.: 10235 Cov.: 31

Gnomad AFR AF: 0.0747

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.398 AC: 64488 AN: 161836 Hom.: 15014 Cov.: 2 AF XY: 0.389 AC XY: 32438 AN XY: 83408

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.535

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.868

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.494

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.316 AC: 47976 AN: 151770 Hom.: 10245 Cov.: 31 AF XY: 0.324 AC XY: 24026 AN XY: 74158

Gnomad4 AFR AF: 0.0746

Gnomad4 AMR AF: 0.480

Gnomad4 ASJ AF: 0.423

Gnomad4 EAS AF: 0.868

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.491

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.343

Alfa AF: 0.366 Hom.: 11071

Bravo AF: 0.317

Asia WGS AF: 0.453 AC: 1573 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.7
DANN	Benign	0.71

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: rs4787645; hg19: chr16-30457350; COSMIC: COSV72100740;