Genetic Variant ANGPT1:p.His477Gln (chr8-107251921-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001146.5(ANGPT1):c.1431C>G(p.His477Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H477H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ANGPT1
NM_001146.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.662

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5 link	c.1431C>G	p.His477Gln	missense_variant	Exon 9 of 9	ENST00000517746.6	NP_001137.2	Q15389-1
ANGPT1	NM_001199859.3 link	c.1428C>G	p.His476Gln	missense_variant	Exon 9 of 9		NP_001186788.1	Q15389-2
ANGPT1	NM_001314051.2 link	c.831C>G	p.His277Gln	missense_variant	Exon 8 of 8		NP_001300980.1	Q15389B4DTQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6 link	c.1431C>G	p.His477Gln	missense_variant	Exon 9 of 9	1	NM_001146.5	ENSP00000428340.1		Q15389-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111872

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;.;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.3

L;.;.;.

PhyloP100

0.66

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.034

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.80

MutPred

0.49

Gain of MoRF binding (P = 0.0814);.;.;.;

MVP

0.93

MPC

2.1

ClinPred

0.97

GERP RS

1.6

Varity_R

0.87

Mutation Taster

=18/82

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over