Genetic Variant TIE1:p.Arg38Leu (chr1-43304905-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005424.5(TIE1):c.113G>T(p.Arg38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TIE1
NM_005424.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIE1	NM_005424.5 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 23	ENST00000372476.8	NP_005415.1	P35590-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TIE1	ENST00000372476.8 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 23	1	NM_005424.5	ENSP00000361554.3	P35590-1
TIE1	ENST00000538015.1 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 8	1			P35590-2
TIE1	ENST00000485125.1 link	n.119G>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1281968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

622496

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113G>T (p.R38L) alteration is located in exon 2 (coding exon 2) of the TIE1 gene. This alteration results from a G to T substitution at nucleotide position 113, causing the arginine (R) at amino acid position 38 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.049

Eigen_PC

Benign

-0.025

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.55

N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.0

N;D

REVEL

Benign

0.15

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.065

B;.

Vest4

0.70

MutPred

0.50

Loss of catalytic residue at R38 (P = 0.1659);Loss of catalytic residue at R38 (P = 0.1659);

MVP

0.80

MPC

0.59

ClinPred

0.86

GERP RS

3.6

Varity_R

0.17

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over