8-107264287-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001146.5(ANGPT1):c.1270G>A(p.Asp424Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000287 in 1,461,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

ANGPT1
NM_001146.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.85

Publications

1 publications found

Variant links:

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)

ANGPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19172683).

BS2

High AC in GnomAdExome4 at 42 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5 link	c.1270G>A	p.Asp424Asn	missense_variant	Exon 8 of 9	ENST00000517746.6	NP_001137.2	Q15389-1
ANGPT1	NM_001199859.3 link	c.1267G>A	p.Asp423Asn	missense_variant	Exon 8 of 9		NP_001186788.1	Q15389-2
ANGPT1	NM_001314051.2 link	c.670G>A	p.Asp224Asn	missense_variant	Exon 7 of 8		NP_001300980.1	Q15389B4DTQ9
ANGPT1	XM_047421699.1 link	c.1103G>A	p.Ter368Ter	stop_retained_variant	Exon 7 of 7		XP_047277655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6 link	c.1270G>A	p.Asp424Asn	missense_variant	Exon 8 of 9	1	NM_001146.5	ENSP00000428340.1		Q15389-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000637

AC:

AN:

251188

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000487

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111916

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 424 of the ANGPT1 protein (p.Asp424Asn). This variant is present in population databases (rs753406610, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ANGPT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

D;D;D;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.67

N;.;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.78

N;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.43

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.0030

B;.;.;.

Vest4

0.16

MutPred

0.36

Loss of stability (P = 0.1489);.;.;.;

MVP

0.54

MPC

0.96

ClinPred

0.10

GERP RS

5.1

Varity_R

0.50

Mutation Taster

=69/31

polymorphism

(source)

Splicing

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

Publications

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8-107264287-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over