8-107289570-G-T

Variant names:

• chr8-107289570-G-T
• rs4324901
• NM_001146.5:c.1038+4366C>A

Variant summary

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

The NM_001146.5(ANGPT1):​c.1038+4366C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 151,932 control chromosomes in the GnomAD database, including 7,303 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 0.28 (7303 hom., cov: 32)
• Consequence: ANGPT1 NM_001146.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5	c.1038+4366C>A		intron_variant	Intron 6 of 8	ENST00000517746.6	NP_001137.2
ANGPT1	NM_001199859.3	c.1035+4366C>A		intron_variant	Intron 6 of 8		NP_001186788.1
ANGPT1	NM_001314051.2	c.438+4366C>A		intron_variant	Intron 5 of 7		NP_001300980.1
ANGPT1	XM_047421699.1	c.1038+4366C>A		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.1038+4366C>A		intron_variant	Intron 6 of 8	1	NM_001146.5	ENSP00000428340.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42694 AN: 151812 Hom.: 7301 Cov.: 32

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.281 AC: 42693 AN: 151932 Hom.: 7303 Cov.: 32 AF XY: 0.280 AC XY: 20758 AN XY: 74260

African (AFR) AF: 0.0705 AC: 2924 AN: 41492

American (AMR) AF: 0.391 AC: 5959 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3462

East Asian (EAS) AF: 0.330 AC: 1705 AN: 5166

South Asian (SAS) AF: 0.317 AC: 1527 AN: 4812

European-Finnish (FIN) AF: 0.323 AC: 3413 AN: 10552

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25021 AN: 67886

Other (OTH) AF: 0.305 AC: 641 AN: 2104

Alfa AF: 0.342 Hom.: 25311

Bravo AF: 0.280

Asia WGS AF: 0.295 AC: 1026 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.53
PhyloP100		0.0040
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: rs4324901; hg19: chr8-108301798;