dbSNP rs1199039: TIE1:p.Leu991Leu (chr1-43319285-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.19

Publications

32 publications found

Variant links:

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

TIE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIE1	NM_005424.5 link	c.2973A>G	p.Leu991Leu	synonymous_variant	Exon 18 of 23	ENST00000372476.8	NP_005415.1	P35590-1
TIE1	NM_001253357.2 link	c.2838A>G	p.Leu946Leu	synonymous_variant	Exon 18 of 23		NP_001240286.1	B4DTW8
TIE1	XM_005271163.3 link	c.2844A>G	p.Leu948Leu	synonymous_variant	Exon 17 of 22		XP_005271220.1
TIE1	XM_047429343.1 link	c.2973A>G	p.Leu991Leu	synonymous_variant	Exon 18 of 20		XP_047285299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIE1	ENST00000372476.8 link	c.2973A>G	p.Leu991Leu	synonymous_variant	Exon 18 of 23	1	NM_005424.5	ENSP00000361554.3		P35590-1

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

47630

AN:

151596

Hom.:

8026

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.358

AC XY:

260543

AN XY:

727096

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

17537

35075

52612

70150

87687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13382

26764

40146

53528

66910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.314

AC:

47676

AN:

151714

Hom.:

8031

Cov.:

AF XY:

0.311

AC XY:

23025

AN XY:

74152

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1591

3182

4774

6365

7956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over