12-108623838-G-A

Position:

• chr12-108623838-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000550948.2(SELPLG):​c.470C>T​(p.Thr157Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,585,782 control chromosomes in the GnomAD database, including 16 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (8 hom.)
• Consequence: SELPLG ENST00000550948.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.17

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038931072).
• BP6: Variant 12-108623838-G-A is Benign according to our data. Variant chr12-108623838-G-A is described in ClinVar as [Benign]. Clinvar id is 787930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00651 (988/151706) while in subpopulation AFR AF= 0.0211 (870/41302). AF 95% confidence interval is 0.0199. There are 8 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELPLG	NM_003006.4	c.470C>T	p.Thr157Met	missense_variant	2/2	ENST00000550948.2	NP_002997.2
SELPLG	NM_001206609.2	c.518C>T	p.Thr173Met	missense_variant	2/2		NP_001193538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELPLG	ENST00000550948.2	c.470C>T	p.Thr157Met	missense_variant	2/2	1	NM_003006.4	ENSP00000447752	P2
SELPLG	ENST00000228463.6	c.518C>T	p.Thr173Met	missense_variant	2/2	2		ENSP00000228463	A2
SELPLG	ENST00000388962.4	c.440C>T	p.Thr147Met	missense_variant	2/2	5		ENSP00000373614	A2

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 976 AN: 151588 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00571

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00182 AC: 457 AN: 251350 Hom.: 2 AF XY: 0.00146 AC XY: 199 AN XY: 135864

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000850 AC: 1219 AN: 1434076 Hom.: 8 Cov.: 32 AF XY: 0.000812 AC XY: 578 AN XY: 711860

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000334

Gnomad4 SAS exome AF: 0.000468

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00651 AC: 988 AN: 151706 Hom.: 8 Cov.: 32 AF XY: 0.00657 AC XY: 487 AN XY: 74168

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00571

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00723

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.074
DANN	Benign	0.97
DEOGEN2	Benign	0.084	T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.40	T;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.16	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.061
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.063	T;T;T
Polyphen		0.42	B;.;.
Vest4		0.072
MVP		0.42
MPC		0.11
ClinPred		0.0049	T
GERP RS		2.5
Varity_R		0.016
gMVP		0.094

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: rs112473865; hg19: chr12-109017614; COSMIC: COSV57311382; COSMIC: COSV57311382;