Genetic Variant NM_001146.5:c.1337-30T>C (chr8-107252045-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001146.5(ANGPT1):c.1337-30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 1,589,926 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 323 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 322 hom. )

Consequence

ANGPT1
NM_001146.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.10

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 8-107252045-A-G is Benign according to our data. Variant chr8-107252045-A-G is described in ClinVar as [Benign]. Clinvar id is 1247640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5 link	c.1337-30T>C	intron_variant	Intron 8 of 8	ENST00000517746.6	NP_001137.2	Q15389-1
ANGPT1	NM_001199859.3 link	c.1334-30T>C	intron_variant	Intron 8 of 8		NP_001186788.1	Q15389-2
ANGPT1	NM_001314051.2 link	c.737-30T>C	intron_variant	Intron 7 of 7		NP_001300980.1	Q15389B4DTQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6 link	c.1337-30T>C		intron_variant	Intron 8 of 8	1	NM_001146.5	ENSP00000428340.1		Q15389-1

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5641

AN:

152102

Hom.:

324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000912

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0117

AC:

2799

AN:

239940

Hom.:

133

AF XY:

0.00941

AC XY:

1221

AN XY:

129810

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.00773

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000246

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00793

GnomAD4 exome

AF:

0.00495

AC:

7110

AN:

1437710

Hom.:

322

Cov.:

AF XY:

0.00456

AC XY:

3254

AN XY:

713114

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.00865

Gnomad4 ASJ exome

AF:

0.0335

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.0000759

Gnomad4 NFE exome

AF:

0.000639

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.0371

AC:

5648

AN:

152216

Hom.:

323

Cov.:

AF XY:

0.0350

AC XY:

2608

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.0288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000912

Gnomad4 OTH

AF:

0.0228

Alfa

AF:

0.0254

Hom.:

Bravo

AF:

0.0417

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.2

DANN

Benign

0.85

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over