12-51912437-C-T

Position:

chr12-51912437-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/13 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACVRL1. . Gene score misZ 2.4458 (greater than the threshold 3.09). Trascript score misZ 3.1363 (greater than threshold 3.09). GenCC has associacion of gene with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.

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. Variant chr12-51912437-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
ACVRL1	NM_000020.3 linkuse as main transcript	c.-5-33C>T		intron_variant		ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9 linkuse as main transcript	c.-5-33C>T		intron_variant		1	NM_000020.3	P1

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

GnomAD3 exomes

AF:

0.0838

AC:

21002

AN:

250560

Hom.:

938

AF XY:

0.0823

AC XY:

11158

AN XY:

135504

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 SAS exome

AF:

0.0571

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

Gnomad4 AFR exome

AF:

0.0627

Gnomad4 AMR exome

AF:

0.0919

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.118

Gnomad4 SAS exome

AF:

0.0595

Gnomad4 FIN exome

AF:

0.104

Gnomad4 NFE exome

AF:

0.0808

Gnomad4 OTH exome

AF:

0.0787

GnomAD4 genome

AF:

0.0769

AC:

11710

AN:

152240

Hom.:

488

Cov.:

AF XY:

0.0764

AC XY:

5687

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0628

Gnomad4 AMR

AF:

0.0802

Gnomad4 ASJ

AF:

0.0943

Gnomad4 EAS

AF:

0.0942

Gnomad4 SAS

AF:

0.0543

Gnomad4 FIN

AF:

0.0955

Gnomad4 NFE

AF:

0.0817

Gnomad4 OTH

AF:

0.0804

Alfa

AF:

0.0777

Hom.:

105

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2013

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

1.0

P;P;P

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

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

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