1-43305070-T-G

Variant names:

• chr1-43305070-T-G
• rs1646713019
• NM_005424.5:c.278T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005424.5(TIE1):​c.278T>G​(p.Phe93Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIE1 NM_005424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIE1	NM_005424.5	c.278T>G	p.Phe93Cys	missense_variant	Exon 2 of 23	ENST00000372476.8	NP_005415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIE1	ENST00000372476.8	c.278T>G	p.Phe93Cys	missense_variant	Exon 2 of 23	1	NM_005424.5	ENSP00000361554.3
TIE1	ENST00000538015.1	c.278T>G	p.Phe93Cys	missense_variant	Exon 2 of 8	1
TIE1	ENST00000485125.1	n.284T>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.278T>G (p.F93C) alteration is located in exon 2 (coding exon 2) of the TIE1 gene. This alteration results from a T to G substitution at nucleotide position 278, causing the phenylalanine (F) at amino acid position 93 to be replaced by a cysteine (C). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.057	T;D
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.39		Loss of MoRF binding (P = 0.0897);Loss of MoRF binding (P = 0.0897);
MVP		0.91
MPC		0.94
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.22
gMVP		0.89

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: rs1646713019; hg19: chr1-43770741;