8-107251893-G-C

Variant names:

• chr8-107251893-G-C
• rs771962601
• NM_001146.5:c.1459C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001146.5(ANGPT1):​c.1459C>G​(p.Arg487Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ANGPT1 NM_001146.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1459C>G	p.Arg487Gly	missense	Exon 9 of 9	NP_001137.2
	ANGPT1	NM_001199859.3		c.1456C>G	p.Arg486Gly	missense	Exon 9 of 9	NP_001186788.1	Q15389-2
	ANGPT1	NM_001314051.2		c.859C>G	p.Arg287Gly	missense	Exon 8 of 8	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.1459C>G	p.Arg487Gly	missense	Exon 9 of 9	ENSP00000428340.1	Q15389-1
	ANGPT1	ENST00000297450.7	TSL:1	c.1456C>G	p.Arg486Gly	missense	Exon 9 of 9	ENSP00000297450.3	Q15389-2
	ANGPT1	ENST00000520734.5	TSL:2	c.859C>G	p.Arg287Gly	missense	Exon 8 of 8	ENSP00000430750.1	B4DTQ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461666 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.88	P
Vest4		0.39
MutPred		0.65		Loss of MoRF binding (P = 0.0109)
MVP		0.62
MPC		2.0
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.74
Mutation Taster		=9/91	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771962601; hg19: chr8-108264121;