1-169594707-C-A

Variant names:

• chr1-169594707-C-A
• rs566756291
• NM_003005.4:c.2272G>T

Variant summary

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

The NM_003005.4(SELP):​c.2272G>T​(p.Val758Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SELP NM_003005.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.929

Genes affected

SELP (HGNC:10721): (selectin P) This gene encodes a 140 kDa protein that is stored in the alpha-granules of platelets and Weibel-Palade bodies of endothelial cells. This protein redistributes to the plasma membrane during platelet activation and degranulation and mediates the interaction of activated endothelial cells or platelets with leukocytes. The membrane protein is a calcium-dependent receptor that binds to sialylated forms of Lewis blood group carbohydrate antigens on neutrophils and monocytes. Alternative splice variants may occur but are not well documented. [provided by RefSeq, Jul 2008]

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=0.08328658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELP	NM_003005.4	c.2272G>T	p.Val758Leu	missense_variant	Exon 13 of 17	ENST00000263686.11	NP_002996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELP	ENST00000263686.11	c.2272G>T	p.Val758Leu	missense_variant	Exon 13 of 17	1	NM_003005.4	ENSP00000263686.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250434 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460910 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726752

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33418

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44608

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26088

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39690

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86124

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53402

Gnomad4 NFE exome AF: 0.00000630 AC: 7 AN: 1111496

Gnomad4 Remaining exome AF: 0.0000332 AC: 2 AN: 60328

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000655 AC: 0.0000654707 AN: 0.0000654707

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000394 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2272G>T (p.V758L) alteration is located in exon 13 (coding exon 13) of the SELP gene. This alteration results from a G to T substitution at nucleotide position 2272, causing the valine (V) at amino acid position 758 to be replaced by a leucine (L). 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	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.012
DANN	Benign	0.79
DEOGEN2	Benign	0.0092	T;.;T;T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.083	T;T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N;N;N;.;N
REVEL	Benign	0.071
Sift	Benign	0.47	T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Vest4		0.15, 0.18, 0.19, 0.19
MutPred		0.33		.;Loss of glycosylation at T757 (P = 0.0854);.;.;.;
MVP		0.29
MPC		0.060
ClinPred		0.048	T
GERP RS		-6.1
gMVP		0.18
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs566756291; hg19: chr1-169563945;