1-43305007-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005424.5(TIE1):c.215C>A(p.Thr72Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,392,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIE1 NM_005424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23578903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIE1	NM_005424.5	c.215C>A	p.Thr72Asn	missense_variant	2/23	ENST00000372476.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIE1	ENST00000372476.8	c.215C>A	p.Thr72Asn	missense_variant	2/23	1	NM_005424.5	P1
TIE1	ENST00000538015.1	c.215C>A	p.Thr72Asn	missense_variant	2/8	1
TIE1	ENST00000485125.1	n.221C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1392734 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 684964

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: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.29e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2023

The c.215C>A (p.T72N) alteration is located in exon 2 (coding exon 2) of the TIE1 gene. This alteration results from a C to A substitution at nucleotide position 215, causing the threonine (T) at amino acid position 72 to be replaced by an asparagine (N). 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	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Benign	0.79
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.077
Sift	Benign	0.74	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.47	P;.
Vest4		0.42
MutPred		0.17		Gain of catalytic residue at T72 (P = 0.0203);Gain of catalytic residue at T72 (P = 0.0203);
MVP		0.82
MPC		0.73
ClinPred		0.55	D
GERP RS		3.9
Varity_R		0.10
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs1470398107; hg19: chr1-43770678;