12-108623772-G-C

Variant names:

• chr12-108623772-G-C
• rs765784409
• NM_003006.4:c.536C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003006.4(SELPLG):​c.536C>G​(p.Thr179Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T179M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SELPLG NM_003006.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16524404).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003006.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELPLG	NM_003006.4	MANE Select	c.536C>G	p.Thr179Arg	missense	Exon 2 of 2	NP_002997.2	Q14242-1
	SELPLG	NM_001206609.2		c.584C>G	p.Thr195Arg	missense	Exon 2 of 2	NP_001193538.1	Q14242-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELPLG	ENST00000550948.2	TSL:1 MANE Select	c.536C>G	p.Thr179Arg	missense	Exon 2 of 2	ENSP00000447752.1	Q14242-1
	SELPLG	ENST00000228463.7	TSL:2	c.584C>G	p.Thr195Arg	missense	Exon 2 of 2	ENSP00000228463.6	Q14242-2
	SELPLG	ENST00000884614.1		c.536C>G	p.Thr179Arg	missense	Exon 2 of 2	ENSP00000554673.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461014 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111634

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		-1.3
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.018
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.068	T
Polyphen		0.88	P
Vest4		0.18
MutPred		0.33		Gain of catalytic residue at P175 (P = 0.0011)
MVP		0.51
MPC		0.12
ClinPred		0.49	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.33
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs765784409; hg19: chr12-109017548;