NM_000020.3:c.314-35A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000020.3(ACVRL1):c.314-35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,579,214 control chromosomes in the GnomAD database, including 158,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16787 hom., cov: 32)

Exomes 𝑓: 0.44 ( 141297 hom. )

Consequence

ACVRL1
NM_000020.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.227

Publications

25 publications found

Variant links:

Genes affected

ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]

ACVRL1 Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
hereditary hemorrhagic telangiectasia
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACVRL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 12-51913524-A-G is Benign according to our data. Variant chr12-51913524-A-G is described in ClinVar as Benign. ClinVar VariationId is 254710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3 link	c.314-35A>G		intron_variant	Intron 3 of 9	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9 link	c.314-35A>G		intron_variant	Intron 3 of 9	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes

AF:

0.463

AC:

70261

AN:

151906

Hom.:

16775

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.330

Gnomad ASJ

AF:

0.484

Gnomad EAS

AF:

0.276

Gnomad SAS

AF:

0.468

Gnomad FIN

AF:

0.455

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.450

Gnomad OTH

AF:

0.440

GnomAD2 exomes

AF:

0.404

AC:

82874

AN:

204938

AF XY:

0.415

show subpopulations

Gnomad AFR exome

AF:

0.551

Gnomad AMR exome

AF:

0.215

Gnomad ASJ exome

AF:

0.479

Gnomad EAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.443

Gnomad NFE exome

AF:

0.441

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.441

AC:

629800

AN:

1427190

Hom.:

141297

Cov.:

AF XY:

0.443

AC XY:

314268

AN XY:

708856

show subpopulations

African (AFR)

AF:

0.563

AC:

18490

AN:

32840

American (AMR)

AF:

0.228

AC:

9813

AN:

43024

Ashkenazi Jewish (ASJ)

AF:

0.479

AC:

12335

AN:

25744

East Asian (EAS)

AF:

0.265

AC:

10191

AN:

38494

South Asian (SAS)

AF:

0.464

AC:

38659

AN:

83244

European-Finnish (FIN)

AF:

0.440

AC:

16381

AN:

37192

Middle Eastern (MID)

AF:

0.451

AC:

1885

AN:

4176

European-Non Finnish (NFE)

AF:

0.449

AC:

495648

AN:

1103072

Other (OTH)

AF:

0.444

AC:

26398

AN:

59404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

21720

43440

65161

86881

108601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14910

29820

44730

59640

74550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.463

AC:

70314

AN:

152024

Hom.:

16787

Cov.:

AF XY:

0.460

AC XY:

34146

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.555

AC:

23023

AN:

41476

American (AMR)

AF:

0.329

AC:

5035

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

1681

AN:

3470

East Asian (EAS)

AF:

0.277

AC:

1426

AN:

5152

South Asian (SAS)

AF:

0.468

AC:

2250

AN:

4810

European-Finnish (FIN)

AF:

0.455

AC:

4816

AN:

10576

Middle Eastern (MID)

AF:

0.476

AC:

140

AN:

294

European-Non Finnish (NFE)

AF:

0.450

AC:

30583

AN:

67930

Other (OTH)

AF:

0.439

AC:

925

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1922

3844

5766

7688

9610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.458

Hom.:

3005

Bravo

AF:

0.451

Asia WGS

AF:

0.392

AC:

1365

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Benign:3

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16179574, 16776339, 25847705) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.90

CADD

Benign

7.5

(source)

DANN

Benign

0.31

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over