8-107252045-A-G

Variant names:

• chr8-107252045-A-G
• rs10088493
• NM_001146.5:c.1337-30T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001146.5(ANGPT1):​c.1337-30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 1,589,926 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (323 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (322 hom.)
• Consequence: ANGPT1 NM_001146.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-107252045-A-G is Benign according to our data. Variant chr8-107252045-A-G is described in ClinVar as Benign. ClinVar VariationId is 1247640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146.5. 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
	ANGPT1	NM_001146.5	MANE Select	c.1337-30T>C		intron	N/A	NP_001137.2
	ANGPT1	NM_001199859.3		c.1334-30T>C		intron	N/A	NP_001186788.1	Q15389-2
	ANGPT1	NM_001314051.2		c.737-30T>C		intron	N/A	NP_001300980.1	B4DTQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT1	ENST00000517746.6	TSL:1 MANE Select	c.1337-30T>C		intron	N/A	ENSP00000428340.1	Q15389-1
	ANGPT1	ENST00000297450.7	TSL:1	c.1334-30T>C		intron	N/A	ENSP00000297450.3	Q15389-2
	ANGPT1	ENST00000520734.5	TSL:2	c.737-30T>C		intron	N/A	ENSP00000430750.1	B4DTQ9

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5641 AN: 152102 Hom.: 324 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0117 AC: 2799 AN: 239940 AF XY: 0.00941

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00793

GnomAD4 exome AF: 0.00495 AC: 7110 AN: 1437710 Hom.: 322 Cov.: 29 AF XY: 0.00456 AC XY: 3254 AN XY: 713114

African (AFR) AF: 0.135 AC: 4404 AN: 32710

American (AMR) AF: 0.00865 AC: 364 AN: 42092

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 845 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.000313 AC: 26 AN: 83036

European-Finnish (FIN) AF: 0.0000759 AC: 4 AN: 52714

Middle Eastern (MID) AF: 0.0152 AC: 86 AN: 5650

European-Non Finnish (NFE) AF: 0.000639 AC: 701 AN: 1097576

Other (OTH) AF: 0.0115 AC: 680 AN: 59340

GnomAD4 genome AF: 0.0371 AC: 5648 AN: 152216 Hom.: 323 Cov.: 32 AF XY: 0.0350 AC XY: 2608 AN XY: 74432

African (AFR) AF: 0.126 AC: 5212 AN: 41518

American (AMR) AF: 0.0144 AC: 220 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68008

Other (OTH) AF: 0.0228 AC: 48 AN: 2106

Alfa AF: 0.0225 Hom.: 49

Bravo AF: 0.0417

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.2
DANN	Benign	0.85
PhyloP100		1.1
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: rs10088493; hg19: chr8-108264273;