8-107302743-T-G

Variant names:

• chr8-107302743-T-G
• rs4133395
• NM_001146.5:c.936+497A>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.936+497A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 151,782 control chromosomes in the GnomAD database, including 13,477 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 0.42 (13477 hom., cov: 32)
• Consequence: ANGPT1 NM_001146.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.481
• Publications: 9 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=-0.69).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5	c.936+497A>C		intron_variant	Intron 5 of 8	ENST00000517746.6	NP_001137.2
ANGPT1	NM_001199859.3	c.933+497A>C		intron_variant	Intron 5 of 8		NP_001186788.1
ANGPT1	NM_001314051.2	c.336+497A>C		intron_variant	Intron 4 of 7		NP_001300980.1
ANGPT1	XM_047421699.1	c.936+497A>C		intron_variant	Intron 5 of 6		XP_047277655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6	c.936+497A>C		intron_variant	Intron 5 of 8	1	NM_001146.5	ENSP00000428340.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63049 AN: 151664 Hom.: 13463 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.416 AC: 63102 AN: 151782 Hom.: 13477 Cov.: 32 AF XY: 0.417 AC XY: 30938 AN XY: 74186

African (AFR) AF: 0.492 AC: 20401 AN: 41442

American (AMR) AF: 0.371 AC: 5633 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1759 AN: 3466

East Asian (EAS) AF: 0.158 AC: 813 AN: 5146

South Asian (SAS) AF: 0.328 AC: 1583 AN: 4822

European-Finnish (FIN) AF: 0.445 AC: 4710 AN: 10578

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 26969 AN: 67834

Other (OTH) AF: 0.429 AC: 901 AN: 2100

Alfa AF: 0.401 Hom.: 21398

Bravo AF: 0.413

Asia WGS AF: 0.300 AC: 1047 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.6
DANN	Benign	0.82
PhyloP100		-0.48
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: rs4133395; hg19: chr8-108314971;