rs1060503242

Positions:

• chr12-51916035-G-A
• chr12-51916035-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1049-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 NM_000020.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.130291 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of 23, new splice context is: tggctgtgatgcactcacAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51916035-G-A is Pathogenic according to our data. Variant chr12-51916035-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.1049-1G>A		splice_acceptor_variant		ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1049-1G>A		splice_acceptor_variant		1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ACVRL1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

The ACVRL1 c.1049-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, along with the ACVRL1 c.841G>T (p.Glu281*) variant, was reported in an individual with hereditary hemorrhagic telangiectasia (Richards-Yutz et al. 2010. PubMed ID: 20414677). It was suggested that the c.841G>T and c.1049-1G>A variants were likely on the same allele; however, no additional studies were conducted to determine phase. This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in ACVRL1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 08, 2023

This sequence change affects an acceptor splice site in intron 7 of the ACVRL1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 20414677; Invitae). ClinVar contains an entry for this variant (Variation ID: 411308). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2023

Identified in individuals with HHT referred for genetic testing at GeneDx and in published literature; these individuals also harbor a second ACVRL1 variant, p.(E281X), though it is unknown if they are present on the same allele or opposite alleles (Richards-Yutz et al., 2010); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20414677) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The c.1049-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 7 of the ACVRL1 gene. This alteration has been reported in a hereditary hemorrhagic telangiectasia cohort (Richards-Yutz J et al. Hum Genet, 2010 Jul;128:61-77). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503242; hg19: chr12-52309819;