12-108623256-A-C

Position:

• chr12-108623256-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003006.4(SELPLG):​c.1052T>G​(p.Met351Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 33)
• Consequence: SELPLG NM_003006.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.37

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042173088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELPLG	NM_003006.4	c.1052T>G	p.Met351Arg	missense_variant	2/2	ENST00000550948.2	NP_002997.2
SELPLG	NM_001206609.2	c.1100T>G	p.Met367Arg	missense_variant	2/2		NP_001193538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELPLG	ENST00000550948.2	c.1052T>G	p.Met351Arg	missense_variant	2/2	1	NM_003006.4	ENSP00000447752.1
SELPLG	ENST00000228463.6	c.1100T>G	p.Met367Arg	missense_variant	2/2	2		ENSP00000228463.6
SELPLG	ENST00000388962.4	c.1022T>G	p.Met341Arg	missense_variant	2/2	5		ENSP00000373614.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.1052T>G (p.M351R) alteration is located in exon 2 (coding exon 1) of the SELPLG gene. This alteration results from a T to G substitution at nucleotide position 1052, causing the methionine (M) at amino acid position 351 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.5
DANN	Benign	0.84
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.024
Sift	Benign	0.18	T;T;T
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.026	B;.;.
Vest4		0.16
MutPred		0.48		Gain of MoRF binding (P = 0.0084);.;.;
MVP		0.13
MPC		0.21
ClinPred		0.040	T
GERP RS		-4.9
Varity_R		0.13
gMVP		0.064

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: rs1001734652; hg19: chr12-109017032;