1-43305342-C-T

Variant names:

• chr1-43305342-C-T
• rs201801618
• NM_005424.5:c.483C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_005424.5(TIE1):​c.483C>T​(p.Asn161Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,494,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: TIE1 NM_005424.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.003036
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308
• Publications: 2 publications found

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: AD, Unknown Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-43305342-C-T is Benign according to our data. Variant chr1-43305342-C-T is described in ClinVar as Benign. ClinVar VariationId is 780767.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BS2: High AC in GnomAd4 at 264 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005424.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIE1	NM_005424.5	MANE Select	c.483C>T	p.Asn161Asn	splice_region synonymous	Exon 3 of 23	NP_005415.1	P35590-1
	TIE1	NM_001253357.2		c.348C>T	p.Asn116Asn	splice_region synonymous	Exon 3 of 23	NP_001240286.1	B4DTW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIE1	ENST00000372476.8	TSL:1 MANE Select	c.483C>T	p.Asn161Asn	splice_region synonymous	Exon 3 of 23	ENSP00000361554.3	P35590-1
	TIE1	ENST00000538015.2	TSL:1	n.483C>T		splice_region non_coding_transcript_exon	Exon 3 of 8
	TIE1	ENST00000964802.1		c.483C>T	p.Asn161Asn	splice_region synonymous	Exon 3 of 22	ENSP00000634861.1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 264 AN: 81280 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000881

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000483

Gnomad OTH AF: 0.00326

GnomAD2 exomes AF: 0.00142 AC: 116 AN: 81962 AF XY: 0.00122

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.000652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000463

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000213 AC: 301 AN: 1412902 Hom.: 1 Cov.: 31 AF XY: 0.000193 AC XY: 134 AN XY: 695520

African (AFR) AF: 0.00729 AC: 238 AN: 32652

American (AMR) AF: 0.000362 AC: 15 AN: 41380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23576

East Asian (EAS) AF: 0.00 AC: 0 AN: 38678

South Asian (SAS) AF: 0.0000255 AC: 2 AN: 78418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51574

Middle Eastern (MID) AF: 0.000537 AC: 3 AN: 5584

European-Non Finnish (NFE) AF: 0.0000148 AC: 16 AN: 1082698

Other (OTH) AF: 0.000463 AC: 27 AN: 58342

GnomAD4 genome AF: 0.00324 AC: 264 AN: 81366 Hom.: 0 Cov.: 24 AF XY: 0.00339 AC XY: 133 AN XY: 39280

African (AFR) AF: 0.0137 AC: 250 AN: 18232

American (AMR) AF: 0.000880 AC: 8 AN: 9086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2298

East Asian (EAS) AF: 0.00 AC: 0 AN: 1190

South Asian (SAS) AF: 0.00 AC: 0 AN: 1284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.0000483 AC: 2 AN: 41370

Other (OTH) AF: 0.00323 AC: 4 AN: 1238

Alfa AF: 0.000790 Hom.: 0

Bravo AF: 0.00206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		-0.31
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.14
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

Other links and lift over

dbSNP: rs201801618; hg19: chr1-43771013;