rs4354281

Variant names:

• chr8-107279475-C-G
• rs4354281
• NM_001146.5:c.1205+5207G>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.1205+5207G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 152,080 control chromosomes in the GnomAD database, including 1,709 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 0.14 (1709 hom., cov: 32)
• Consequence: ANGPT1 NM_001146.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.177
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5	c.1205+5207G>C		intron_variant	Intron 7 of 8	ENST00000517746.6	NP_001137.2
ANGPT1	NM_001199859.3	c.1202+5207G>C		intron_variant	Intron 7 of 8		NP_001186788.1
ANGPT1	NM_001314051.2	c.605+5207G>C		intron_variant	Intron 6 of 7		NP_001300980.1
ANGPT1	XM_047421699.1	c.1038+14461G>C		intron_variant	Intron 6 of 6		XP_047277655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6	c.1205+5207G>C		intron_variant	Intron 7 of 8	1	NM_001146.5	ENSP00000428340.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21084 AN: 151962 Hom.: 1707 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0984

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.139 AC: 21102 AN: 152080 Hom.: 1709 Cov.: 32 AF XY: 0.142 AC XY: 10527 AN XY: 74334

African (AFR) AF: 0.110 AC: 4582 AN: 41486

American (AMR) AF: 0.140 AC: 2136 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0984 AC: 341 AN: 3466

East Asian (EAS) AF: 0.351 AC: 1814 AN: 5168

South Asian (SAS) AF: 0.240 AC: 1152 AN: 4808

European-Finnish (FIN) AF: 0.124 AC: 1313 AN: 10572

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9097 AN: 67998

Other (OTH) AF: 0.134 AC: 283 AN: 2114

Alfa AF: 0.134 Hom.: 171

Bravo AF: 0.137

Asia WGS AF: 0.247 AC: 854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.57
PhyloP100		0.18
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: rs4354281; hg19: chr8-108291703;