1-43321766-A-G

Variant names:

• chr1-43321766-A-G
• rs11210834
• NM_005424.5:c.3345+51A>G

Variant summary

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

The NM_005424.5(TIE1):​c.3345+51A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,523,580 control chromosomes in the GnomAD database, including 48,187 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 0.24 (4524 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43663 hom.)
• Consequence: TIE1 NM_005424.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.380
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.404 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.3345+51A>G		intron	N/A	NP_005415.1	P35590-1
	TIE1	NM_001253357.2		c.3210+51A>G		intron	N/A	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.3345+51A>G		intron	N/A	ENSP00000361554.3	P35590-1
	TIE1	ENST00000964802.1		c.3048+51A>G		intron	N/A	ENSP00000634861.1
	TIE1	ENST00000964803.1		c.2787+51A>G		intron	N/A	ENSP00000634862.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36289 AN: 151892 Hom.: 4519 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.269 AC: 41232 AN: 153006 AF XY: 0.272

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.311

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.250 AC: 342227 AN: 1371570 Hom.: 43663 Cov.: 26 AF XY: 0.251 AC XY: 169982 AN XY: 677320

African (AFR) AF: 0.168 AC: 5197 AN: 30984

American (AMR) AF: 0.252 AC: 8974 AN: 35616

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 5999 AN: 24984

East Asian (EAS) AF: 0.378 AC: 13458 AN: 35566

South Asian (SAS) AF: 0.291 AC: 22890 AN: 78640

European-Finnish (FIN) AF: 0.313 AC: 14872 AN: 47590

Middle Eastern (MID) AF: 0.205 AC: 1062 AN: 5186

European-Non Finnish (NFE) AF: 0.242 AC: 255638 AN: 1056076

Other (OTH) AF: 0.248 AC: 14137 AN: 56928

GnomAD4 genome AF: 0.239 AC: 36313 AN: 152010 Hom.: 4524 Cov.: 32 AF XY: 0.242 AC XY: 18008 AN XY: 74314

African (AFR) AF: 0.179 AC: 7432 AN: 41474

American (AMR) AF: 0.227 AC: 3466 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 827 AN: 3470

East Asian (EAS) AF: 0.418 AC: 2159 AN: 5162

South Asian (SAS) AF: 0.294 AC: 1413 AN: 4808

European-Finnish (FIN) AF: 0.309 AC: 3270 AN: 10576

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16981 AN: 67936

Other (OTH) AF: 0.239 AC: 503 AN: 2108

Alfa AF: 0.243 Hom.: 12241

Bravo AF: 0.232

Asia WGS AF: 0.333 AC: 1158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.6
DANN	Benign	0.57
PhyloP100		0.38
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: rs11210834; hg19: chr1-43787437; COSMIC: COSV65249027; COSMIC: COSV65249027;