1-43305293-C-G

Variant names:

• chr1-43305293-C-G
• rs1195994022
• NM_005424.5:c.434C>G

Variant summary

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

The NM_005424.5(TIE1):​c.434C>G​(p.Ser145Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,452,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TIE1 NM_005424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 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	c.434C>G	p.Ser145Cys	missense_variant	Exon 3 of 23	ENST00000372476.8	NP_005415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIE1	ENST00000372476.8	c.434C>G	p.Ser145Cys	missense_variant	Exon 3 of 23	1	NM_005424.5	ENSP00000361554.3
TIE1	ENST00000538015.1	c.434C>G	p.Ser145Cys	missense_variant	Exon 3 of 8	1
TIE1	ENST00000485125.1	n.507C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247644 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1452732 Hom.: 0 Cov.: 31 AF XY: 0.00000971 AC XY: 7 AN XY: 720924

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: 0.0000136

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.434C>G (p.S145C) alteration is located in exon 3 (coding exon 3) of the TIE1 gene. This alteration results from a C to G substitution at nucleotide position 434, causing the serine (S) at amino acid position 145 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	0.062
Eigen_PC	Benign	0.0094
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.62	P;.
Vest4		0.39
MutPred		0.72		Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);
MVP		0.88
MPC		0.62
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.76

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: rs1195994022; hg19: chr1-43770964;