rs72554691

Positions:

• chr5-42808269-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000514985.6(SELENOP):​c.85A>G​(p.Lys29Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,570,408 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0092 (22 hom., cov: 31)
  • Exomes 𝑓: 0.00082 (20 hom.)
• Consequence: SELENOP ENST00000514985.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.737

Genes affected

SELENOP (HGNC:10751): (selenoprotein P) This gene encodes a selenoprotein that is predominantly expressed in the liver and secreted into the plasma. This selenoprotein is unique in that it contains multiple selenocysteine (Sec) residues per polypeptide (10 in human), and accounts for most of the selenium in plasma. It has been implicated as an extracellular antioxidant, and in the transport of selenium to extra-hepatic tissues via apolipoprotein E receptor-2 (apoER2). Mice lacking this gene exhibit neurological dysfunction, suggesting its importance in normal brain function. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. The mRNA for this selenoprotein contains two SECIS elements. The use of alternative polyadenylation sites, one located in between the two SECIS elements, results in two populations of mRNAs containing either both (predominant) or just the upstream SECIS element (PMID:27881738). Alternatively spliced transcript variants have also been found for this gene. [provided by RefSeq, Oct 2018]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004091978).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1400/151756) while in subpopulation AFR AF= 0.0323 (1336/41356). AF 95% confidence interval is 0.0309. There are 22 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENOP	NM_005410.4	c.85A>G	p.Lys29Glu	missense_variant	2/5	ENST00000514985.6	NP_005401.3
SELENOP	NM_001093726.3	c.175A>G	p.Lys59Glu	missense_variant	3/6		NP_001087195.1
SELENOP	NM_001085486.3	c.85A>G	p.Lys29Glu	missense_variant	3/6		NP_001078955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENOP	ENST00000514985.6	c.85A>G	p.Lys29Glu	missense_variant	2/5	1	NM_005410.4	ENSP00000420939	P1

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1398 AN: 151638 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

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: 0.0000736

Gnomad OTH AF: 0.00529

GnomAD3 exomes AF: 0.00210 AC: 468 AN: 222620 Hom.: 8 AF XY: 0.00142 AC XY: 173 AN XY: 121524

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.000908

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.000975

GnomAD4 exome AF: 0.000824 AC: 1169 AN: 1418652 Hom.: 20 Cov.: 28 AF XY: 0.000645 AC XY: 455 AN XY: 705584

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000501

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00923 AC: 1400 AN: 151756 Hom.: 22 Cov.: 31 AF XY: 0.00896 AC XY: 665 AN XY: 74210

Gnomad4 AFR AF: 0.0323

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00523

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.0105

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0325 AC: 121

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 336

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T;T;T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.48	.;.;T;.;.;.
MetaRNN	Benign	0.0041	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.27	N;N;N;.;N;N
REVEL	Benign	0.046
Sift	Benign	0.25	T;T;T;.;T;T
Sift4G	Benign	0.11	T;T;T;T;.;.
Vest4		0.18
MVP		0.076
MPC		0.38
ClinPred		0.032	T
GERP RS		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043

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: rs72554691; hg19: chr5-42808371; COSMIC: COSV99073513; COSMIC: COSV99073513;