Genetic Variant NM_001146.5:c.*949G>C (chr8-107250906-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001146.5(ANGPT1):c.*949G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 151,542 control chromosomes in the GnomAD database, including 31,756 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 0.64 ( 31756 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

ANGPT1
NM_001146.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.932

Publications

14 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5 link	c.*949G>C	3_prime_UTR_variant	Exon 9 of 9	ENST00000517746.6	NP_001137.2	Q15389-1
ANGPT1	NM_001199859.3 link	c.*949G>C	3_prime_UTR_variant	Exon 9 of 9		NP_001186788.1	Q15389-2
ANGPT1	NM_001314051.2 link	c.*949G>C	3_prime_UTR_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.*949G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_001146.5	ENSP00000428340.1		Q15389-1
ANGPT1	ENST00000297450.7 link	c.*949G>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000297450.3		Q15389-2

Frequencies

GnomAD3 genomes

AF:

0.642

AC:

97194

AN:

151428

Hom.:

31729

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.628

Gnomad ASJ

AF:

0.753

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.636

Gnomad FIN

AF:

0.640

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.708

Gnomad OTH

AF:

0.673

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.642

AC:

97277

AN:

151542

Hom.:

31756

Cov.:

AF XY:

0.637

AC XY:

47190

AN XY:

74074

show subpopulations

African (AFR)

AF:

0.555

AC:

22858

AN:

41170

American (AMR)

AF:

0.628

AC:

9551

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.753

AC:

2612

AN:

3468

East Asian (EAS)

AF:

0.428

AC:

2208

AN:

5160

South Asian (SAS)

AF:

0.634

AC:

3057

AN:

4818

European-Finnish (FIN)

AF:

0.640

AC:

6740

AN:

10536

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.708

AC:

48087

AN:

67878

Other (OTH)

AF:

0.670

AC:

1414

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1741

3483

5224

6966

8707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.494

Hom.:

1052

Bravo

AF:

0.638

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.61

(source)

DANN

Benign

0.62

PhyloP100

-0.93

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over