12-51913967-C-G

Variant names:

• chr12-51913967-C-G
• NM_000020.3:c.526-7C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000020.3(ACVRL1):​c.526-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 NM_000020.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: -0.0880

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-51913967-C-G is Pathogenic according to our data. Variant chr12-51913967-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1746471.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.526-7C>G		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.526-7C>G		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Sep 24, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via nonsense-mediated decay (PMID: 16525724); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 16525724, 36981042) -

Cardiovascular phenotype Pathogenic:1

Apr 27, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.526-7C>G intronic variant results from a C to G substitution 7 nucleotides upstream from coding exon 4 in the ACVRL1 gene. The variant has been detected in multiple individuals with definite or suspected diagnosis of hereditary hemorrhagic telangiectasia (Argyriou L et al. Int J Mol Med, 2006 Apr;17:655-9; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Sep 08, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ACVRL1 is an intronic variant located in intron 4. It is observed to cause a profound splicing anomaly, predominantly causing skipping of biologically relevant exons 4-5 (p.Ala105_Gly209delinsArg) and to a lesser degree skipping of exon 5 (p.Gly209Glufs*49) in RNA assays (RNA4RD). The predominant splicing anomaly results in an in-frame deletion (removes amino acids 105-209) that is expected to escape nonsense-mediated decay and truncate a critical functional domain, while the other misplacing event results in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 20301525). This variant is absent from the population database gnomAD v4.1. This variant has been reported in at least three probands with a phenotype consistent with hereditary haemorrhagic telangiectasia (HHT) and segregates with HHT in two families (PMID: 16525724; ClinVar: SCV002641244.2; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Moderate, PM2_Supporting, PP1_Moderate. -

Telangiectasia, hereditary hemorrhagic, type 2 Uncertain:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the ACVRL1 gene. It does not directly change the encoded amino acid sequence of the ACVRL1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary hemorrhagic teleangiectasia (PMID: 16525724). ClinVar contains an entry for this variant (Variation ID: 1746471). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.84		Position offset: 7

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52307751;