rs2991990

Variant names:

• chr1-43314198-T-G
• rs2991990
• NM_005424.5:c.2409+230T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000372476.8(TIE1):​c.2409+230T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 703,858 control chromosomes in the GnomAD database, including 158,621 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 0.70 (37729 hom., cov: 32)
  • Exomes 𝑓: 0.66 (120892 hom.)
• Consequence: TIE1 ENST00000372476.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251
• Publications: 15 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: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372476.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIE1	NM_005424.5	MANE Select	c.2409+230T>G		intron	N/A	NP_005415.1
	TIE1	NM_001253357.2		c.2274+230T>G		intron	N/A	NP_001240286.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIE1	ENST00000372476.8	TSL:1 MANE Select	c.2409+230T>G		intron	N/A	ENSP00000361554.3
	TIE1	ENST00000461061.1	TSL:3	n.430-185T>G		intron	N/A
	TIE1	ENST00000473014.1	TSL:2	n.677+230T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106040 AN: 151992 Hom.: 37701 Cov.: 32

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.647

GnomAD4 exome AF: 0.655 AC: 361436 AN: 551748 Hom.: 120892 Cov.: 7 AF XY: 0.662 AC XY: 187899 AN XY: 283826

African (AFR) AF: 0.829 AC: 12068 AN: 14552

American (AMR) AF: 0.658 AC: 13490 AN: 20486

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 8300 AN: 14174

East Asian (EAS) AF: 0.824 AC: 23052 AN: 27986

South Asian (SAS) AF: 0.833 AC: 39332 AN: 47200

European-Finnish (FIN) AF: 0.669 AC: 17102 AN: 25546

Middle Eastern (MID) AF: 0.618 AC: 1765 AN: 2856

European-Non Finnish (NFE) AF: 0.614 AC: 227527 AN: 370370

Other (OTH) AF: 0.658 AC: 18800 AN: 28578

GnomAD4 genome AF: 0.698 AC: 106122 AN: 152110 Hom.: 37729 Cov.: 32 AF XY: 0.701 AC XY: 52115 AN XY: 74352

African (AFR) AF: 0.830 AC: 34447 AN: 41496

American (AMR) AF: 0.637 AC: 9734 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2030 AN: 3468

East Asian (EAS) AF: 0.857 AC: 4443 AN: 5182

South Asian (SAS) AF: 0.844 AC: 4070 AN: 4824

European-Finnish (FIN) AF: 0.659 AC: 6959 AN: 10566

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42339 AN: 67982

Other (OTH) AF: 0.648 AC: 1368 AN: 2110

Alfa AF: 0.639 Hom.: 37917

Bravo AF: 0.700

Asia WGS AF: 0.849 AC: 2953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.5
DANN	Benign	0.75
PhyloP100		0.25
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: rs2991990; hg19: chr1-43779869;