rs2163870

Variant names:

• chr8-107365673-A-G
• rs2163870
• NM_001146.5:c.298-18576T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001146.5(ANGPT1):​c.298-18576T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,082 control chromosomes in the GnomAD database, including 8,204 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8204 hom., cov: 31)
• Consequence: ANGPT1 NM_001146.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 7 publications found

Genes affected

ANGPT1 (HGNC:484): (angiopoietin 1) This gene encodes a secreted glycoprotein that belongs to the angiopoietin family. Members of this family play important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The protein encoded by this gene is a secreted glycoprotein that activates the receptor by inducing its tyrosine phosphorylation. It plays a critical role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme and inhibits endothelial permeability. The protein also contributes to blood vessel maturation and stability, and may be involved in early development of the heart. Mutations in this gene are associated with hereditary angioedema. [provided by RefSeq, Aug 2020]

ANGPT1 Gene-Disease associations (from GenCC):

• glaucoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary congenital glaucoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• angioedema, hereditary, 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5	c.298-18576T>C		intron_variant	Intron 1 of 8	ENST00000517746.6	NP_001137.2
ANGPT1	NM_001199859.3	c.298-18576T>C		intron_variant	Intron 1 of 8		NP_001186788.1
ANGPT1	XM_047421699.1	c.298-18576T>C		intron_variant	Intron 1 of 6		XP_047277655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6	c.298-18576T>C		intron_variant	Intron 1 of 8	1	NM_001146.5	ENSP00000428340.1
ANGPT1	ENST00000297450.7	c.298-18576T>C		intron_variant	Intron 1 of 8	1		ENSP00000297450.3
ANGPT1	ENST00000520033.1	c.-24-18576T>C		intron_variant	Intron 1 of 1	4		ENSP00000428908.1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48723 AN: 151964 Hom.: 8186 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.321 AC: 48780 AN: 152082 Hom.: 8204 Cov.: 31 AF XY: 0.323 AC XY: 24016 AN XY: 74348

African (AFR) AF: 0.215 AC: 8924 AN: 41492

American (AMR) AF: 0.302 AC: 4608 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1193 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2488 AN: 5162

South Asian (SAS) AF: 0.420 AC: 2025 AN: 4822

European-Finnish (FIN) AF: 0.331 AC: 3502 AN: 10588

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24719 AN: 67972

Other (OTH) AF: 0.315 AC: 665 AN: 2110

Alfa AF: 0.346 Hom.: 17248

Bravo AF: 0.311

Asia WGS AF: 0.413 AC: 1433 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.67
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2163870; hg19: chr8-108377901;