rs1199039

chr1-43319285-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_005424.5(TIE1):c.2973A>G(p.Leu991=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,613,214 control chromosomes in the GnomAD database, including 107,921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.31 (8031 hom., cov: 29)
  • Exomes 𝑓: 0.36 (99890 hom.)
• Consequence: TIE1 NM_005424.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

Genes affected

TIE1 (HGNC:11809): (tyrosine kinase with immunoglobulin like and EGF like domains 1) This gene encodes a member of the tyrosine protein kinase family. The encoded protein plays a critical role in angiogenesis and blood vessel stability by inhibiting angiopoietin 1 signaling through the endothelial receptor tyrosine kinase Tie2. Ectodomain cleavage of the encoded protein relieves inhibition of Tie2 and is mediated by multiple factors including vascular endothelial growth factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-43319285-A-G is Benign according to our data. Variant chr1-43319285-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIE1	NM_005424.5	c.2973A>G	p.Leu991=	synonymous_variant	18/23	ENST00000372476.8
TIE1	NM_001253357.2	c.2838A>G	p.Leu946=	synonymous_variant	18/23
TIE1	XM_005271163.3	c.2844A>G	p.Leu948=	synonymous_variant	17/22
TIE1	XM_047429343.1	c.2973A>G	p.Leu991=	synonymous_variant	18/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIE1	ENST00000372476.8	c.2973A>G	p.Leu991=	synonymous_variant	18/23	1	NM_005424.5	P1
TIE1	ENST00000473014.1	n.1602A>G		non_coding_transcript_exon_variant	3/4	2
TIE1	ENST00000492599.1	n.194A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47630 AN: 151596 Hom.: 8026 Cov.: 29

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.363

GnomAD3 exomes AF: 0.316 AC: 79516 AN: 251444 Hom.: 13775 AF XY: 0.315 AC XY: 42812 AN XY: 135906

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.363 AC: 530367 AN: 1461500 Hom.: 99890 Cov.: 42 AF XY: 0.358 AC XY: 260543 AN XY: 727096

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.320

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.350

GnomAD4 genome AF: 0.314 AC: 47676 AN: 151714 Hom.: 8031 Cov.: 29 AF XY: 0.311 AC XY: 23025 AN XY: 74152

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.361

Alfa AF: 0.369 Hom.: 14033

Bravo AF: 0.313

Asia WGS AF: 0.159 AC: 553 AN: 3478

EpiCase AF: 0.390

EpiControl AF: 0.392

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	12
Dann	Benign	0.66

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: rs1199039; hg19: chr1-43784956; COSMIC: COSV65250738; COSMIC: COSV65250738;