rs1199039

Variant names:

• chr1-43319285-A-G
• rs1199039
• NM_005424.5:c.2973A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005424.5(TIE1):​c.2973A>G​(p.Leu991Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 32 publications found

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]

TIE1 Gene-Disease associations (from GenCC):

• lymphatic malformation 11

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005424.5. 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
	TIE1	NM_005424.5	MANE Select	c.2973A>G	p.Leu991Leu	synonymous	Exon 18 of 23	NP_005415.1	P35590-1
	TIE1	NM_001253357.2		c.2838A>G	p.Leu946Leu	synonymous	Exon 18 of 23	NP_001240286.1	B4DTW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIE1	ENST00000372476.8	TSL:1 MANE Select	c.2973A>G	p.Leu991Leu	synonymous	Exon 18 of 23	ENSP00000361554.3	P35590-1
	TIE1	ENST00000964802.1		c.2676A>G	p.Leu892Leu	synonymous	Exon 17 of 22	ENSP00000634861.1
	TIE1	ENST00000964803.1		c.2415A>G	p.Leu805Leu	synonymous	Exon 14 of 19	ENSP00000634862.1

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

GnomAD2 exomes AF: 0.316 AC: 79516 AN: 251444 AF XY: 0.315

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 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

African (AFR) AF: 0.205 AC: 6862 AN: 33476

American (AMR) AF: 0.320 AC: 14296 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 10993 AN: 26128

East Asian (EAS) AF: 0.180 AC: 7144 AN: 39698

South Asian (SAS) AF: 0.179 AC: 15442 AN: 86258

European-Finnish (FIN) AF: 0.331 AC: 17690 AN: 53416

Middle Eastern (MID) AF: 0.393 AC: 2269 AN: 5768

European-Non Finnish (NFE) AF: 0.391 AC: 434521 AN: 1111662

Other (OTH) AF: 0.350 AC: 21150 AN: 60376

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

African (AFR) AF: 0.203 AC: 8394 AN: 41352

American (AMR) AF: 0.371 AC: 5654 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1443 AN: 3466

East Asian (EAS) AF: 0.150 AC: 771 AN: 5156

South Asian (SAS) AF: 0.164 AC: 783 AN: 4778

European-Finnish (FIN) AF: 0.342 AC: 3611 AN: 10550

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25785 AN: 67860

Other (OTH) AF: 0.361 AC: 756 AN: 2096

Alfa AF: 0.364 Hom.: 16905

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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