NM_001146.5:c.1206-4848G>C

Variant names:

• chr8-107269199-C-G
• rs6993449
• NM_001146.5:c.1206-4848G>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.1206-4848G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 151,730 control chromosomes in the GnomAD database, including 13,804 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 (13804 hom., cov: 31)
• Consequence: ANGPT1 NM_001146.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.435
• Publications: 3 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 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.1206-4848G>C		intron	N/A	NP_001137.2
	ANGPT1	NM_001199859.3		c.1203-4848G>C		intron	N/A	NP_001186788.1	Q15389-2
	ANGPT1	NM_001314051.2		c.606-4848G>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.1206-4848G>C		intron	N/A	ENSP00000428340.1	Q15389-1
	ANGPT1	ENST00000297450.7	TSL:1	c.1203-4848G>C		intron	N/A	ENSP00000297450.3	Q15389-2
	ANGPT1	ENST00000520734.5	TSL:2	c.606-4848G>C		intron	N/A	ENSP00000430750.1	B4DTQ9

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62916 AN: 151612 Hom.: 13776 Cov.: 31

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.387

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

GnomAD4 genome AF: 0.415 AC: 62993 AN: 151730 Hom.: 13804 Cov.: 31 AF XY: 0.420 AC XY: 31102 AN XY: 74126

African (AFR) AF: 0.543 AC: 22452 AN: 41360

American (AMR) AF: 0.423 AC: 6446 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 964 AN: 3466

East Asian (EAS) AF: 0.569 AC: 2929 AN: 5146

South Asian (SAS) AF: 0.412 AC: 1980 AN: 4806

European-Finnish (FIN) AF: 0.379 AC: 4002 AN: 10550

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22937 AN: 67880

Other (OTH) AF: 0.388 AC: 812 AN: 2092

Alfa AF: 0.223 Hom.: 477

Bravo AF: 0.421

Asia WGS AF: 0.498 AC: 1729 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.41
DANN	Benign	0.40
PhyloP100		-0.43
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: rs6993449; hg19: chr8-108281427;