chr12-51912437-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000550683.5(ACVRL1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 1,611,008 control chromosomes in the GnomAD database, including 5,581 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 488 hom., cov: 32)

Exomes 𝑓: 0.081 ( 5093 hom. )

Consequence

ACVRL1
ENST00000550683.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.272

Publications

17 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 -19 ACMG points.

PP2

Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.1363 (above the threshold of 3.09). GenCC associations: The gene is linked to telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028590858).

BP6

Variant 12-51912437-C-T is Benign according to our data. Variant chr12-51912437-C-T is described in ClinVar as [Benign]. Clinvar id is 136292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3 link	c.-5-33C>T		intron_variant	Intron 1 of 9	ENST00000388922.9	NP_000011.2	P37023A0A0S2Z310

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9 link	c.-5-33C>T		intron_variant	Intron 1 of 9	1	NM_000020.3	ENSP00000373574.4		P37023

Frequencies

GnomAD3 genomes

AF:

0.0770

AC:

11709

AN:

152122

Hom.:

487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0629

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.0803

Gnomad ASJ

AF:

0.0943

Gnomad EAS

AF:

0.0942

Gnomad SAS

AF:

0.0540

Gnomad FIN

AF:

0.0955

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0817

Gnomad OTH

AF:

0.0803

GnomAD2 exomes

AF:

0.0838

AC:

21002

AN:

250560

AF XY:

0.0823

show subpopulations

Gnomad AFR exome

AF:

0.0609

Gnomad AMR exome

AF:

0.0959

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.0788

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.0862

Gnomad OTH exome

AF:

0.0825

GnomAD4 exome

AF:

0.0815

AC:

118853

AN:

1458768

Hom.:

5093

Cov.:

AF XY:

0.0808

AC XY:

58625

AN XY:

725826

show subpopulations

African (AFR)

AF:

0.0627

AC:

2095

AN:

33420

American (AMR)

AF:

0.0919

AC:

4107

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2629

AN:

26102

East Asian (EAS)

AF:

0.118

AC:

4677

AN:

39688

South Asian (SAS)

AF:

0.0595

AC:

5128

AN:

86152

European-Finnish (FIN)

AF:

0.104

AC:

5567

AN:

53338

Middle Eastern (MID)

AF:

0.0546

AC:

315

AN:

5768

European-Non Finnish (NFE)

AF:

0.0808

AC:

89587

AN:

1109314

Other (OTH)

AF:

0.0787

AC:

4748

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

5518

11036

16555

22073

27591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0769

AC:

11710

AN:

152240

Hom.:

488

Cov.:

AF XY:

0.0764

AC XY:

5687

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0628

AC:

2608

AN:

41554

American (AMR)

AF:

0.0802

AC:

1227

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0943

AC:

327

AN:

3468

East Asian (EAS)

AF:

0.0942

AC:

487

AN:

5170

South Asian (SAS)

AF:

0.0543

AC:

262

AN:

4826

European-Finnish (FIN)

AF:

0.0955

AC:

1013

AN:

10602

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0817

AC:

5558

AN:

68004

Other (OTH)

AF:

0.0804

AC:

170

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

549

1099

1648

2198

2747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0847

Hom.:

782

Bravo

AF:

0.0768

TwinsUK

AF:

0.0809

AC:

300

ALSPAC

AF:

0.0781

AC:

301

ESP6500AA

AF:

0.0608

AC:

268

ESP6500EA

AF:

0.0841

AC:

723

ExAC

AF:

0.0830

AC:

10074

Asia WGS

AF:

0.0830

AC:

290

AN:

3478

EpiCase

AF:

0.0872

EpiControl

AF:

0.0855

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2

Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 22, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Benign

3.3

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0056

.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-0.78

PhyloP100

0.27

PROVEAN

Benign

-0.43

N;N;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

.;D;T

Polyphen

0.0

.;.;B

Vest4

0.024, 0.094

ClinPred

0.0041

GERP RS

-6.7

PromoterAI

-0.063

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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chr12-51912437-C-T

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