rs2228315

Positions:

• chr12-108624122-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003006.4(SELPLG):​c.186G>A​(p.Met62Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,614,010 control chromosomes in the GnomAD database, including 8,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2308 hom., cov: 32)
  • Exomes 𝑓: 0.078 (6550 hom.)
• Consequence: SELPLG NM_003006.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.977

Genes affected

SELPLG (HGNC:10722): (selectin P ligand) This gene encodes a glycoprotein that functions as a high affinity counter-receptor for the cell adhesion molecules P-, E- and L- selectin expressed on myeloid cells and stimulated T lymphocytes. As such, this protein plays a critical role in leukocyte trafficking during inflammation by tethering of leukocytes to activated platelets or endothelia expressing selectins. This protein requires two post-translational modifications, tyrosine sulfation and the addition of the sialyl Lewis x tetrasaccharide (sLex) to its O-linked glycans, for its high-affinity binding activity. Aberrant expression of this gene and polymorphisms in this gene are associated with defects in the innate and adaptive immune response. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004031837).
• BP6: Variant 12-108624122-C-T is Benign according to our data. Variant chr12-108624122-C-T is described in ClinVar as [Benign]. Clinvar id is 3055988.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELPLG	NM_003006.4	c.186G>A	p.Met62Ile	missense_variant	2/2	ENST00000550948.2	NP_002997.2
SELPLG	NM_001206609.2	c.234G>A	p.Met78Ile	missense_variant	2/2		NP_001193538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELPLG	ENST00000550948.2	c.186G>A	p.Met62Ile	missense_variant	2/2	1	NM_003006.4	ENSP00000447752.1
SELPLG	ENST00000228463.6	c.234G>A	p.Met78Ile	missense_variant	2/2	2		ENSP00000228463.6
SELPLG	ENST00000388962.4	c.186G>A	p.Met62Ile	missense_variant	1/2	5		ENSP00000373614.3

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21285 AN: 152044 Hom.: 2301 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0554

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.113 AC: 28525 AN: 251428 Hom.: 2505 AF XY: 0.104 AC XY: 14139 AN XY: 135886

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.290

Gnomad SAS exome AF: 0.0605

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0670

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0784 AC: 114658 AN: 1461848 Hom.: 6550 Cov.: 34 AF XY: 0.0770 AC XY: 55980 AN XY: 727232

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.0609

Gnomad4 FIN exome AF: 0.0533

Gnomad4 NFE exome AF: 0.0622

Gnomad4 OTH exome AF: 0.0970

GnomAD4 genome AF: 0.140 AC: 21331 AN: 152162 Hom.: 2308 Cov.: 32 AF XY: 0.139 AC XY: 10306 AN XY: 74396

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.0607

Gnomad4 FIN AF: 0.0554

Gnomad4 NFE AF: 0.0639

Gnomad4 OTH AF: 0.124

Alfa AF: 0.0865 Hom.: 2080

Bravo AF: 0.156

TwinsUK AF: 0.0639 AC: 237

ALSPAC AF: 0.0677 AC: 261

ESP6500AA AF: 0.268 AC: 1181

ESP6500EA AF: 0.0676 AC: 581

ExAC AF: 0.113 AC: 13653

Asia WGS AF: 0.148 AC: 514 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SELPLG-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.064
DANN	Benign	0.51
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.26	T;T;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.58	N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.070	N;N;N
REVEL	Benign	0.0040
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.015
MutPred		0.32		Gain of catalytic residue at P59 (P = 2e-04);Gain of catalytic residue at P59 (P = 2e-04);.;
MPC		0.12
ClinPred		0.00058	T
GERP RS		-1.8
Varity_R		0.020
gMVP		0.091

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: rs2228315; hg19: chr12-109017898; COSMIC: COSV57314080; COSMIC: COSV57314080;