rs863223406

Variant names:

• chr12-51919116-G-A
• rs863223406
• NM_000020.3:c.1377+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1377+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.97
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51919116-G-A is Pathogenic according to our data. Variant chr12-51919116-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000020.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	NM_000020.3	MANE Select	c.1377+1G>A		splice_donor intron	N/A	NP_000011.2
	ACVRL1	NM_001406488.1		c.1378G>A	p.Val460Met	missense	Exon 9 of 9	NP_001393417.1
	ACVRL1	NM_001406489.1		c.1378G>A	p.Val460Met	missense	Exon 8 of 8	NP_001393418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.1377+1G>A		splice_donor intron	N/A	ENSP00000373574.4
	ACVRL1	ENST00000550683.5	TSL:1	c.1419+1G>A		splice_donor intron	N/A	ENSP00000447884.1
	ACVRL1	ENST00000551576.6	TSL:1	c.1377+1G>A		splice_donor intron	N/A	ENSP00000455848.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000535 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2

Oct 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 9 of the ACVRL1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 15712270, 19508727, 21158752; Invitae). ClinVar contains an entry for this variant (Variation ID: 212794). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Aug 26, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

May 04, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, PS4_moderate, PVS1

Apr 22, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IVS9+1 G>A : c.1377+1 G>A in intron 9 of the ACVRL1 gene (NM_000020.2). The c.1377+1 G>A mutation has been reported previously in association with HHT, and was absent from 100 control alleles (Kuehl H et al., 2005). Furthermore, the c.1377+1 G>A mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice donor site in intron 9 and is predicted to cause abnormal gene splicing. Other splice site mutations in the ACVRL1 gene have been reported in association with HHT. In summary, c.1377+1 G>A in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA panel(s).

Hereditary hemorrhagic telangiectasia Pathogenic:1

Sep 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ACVRL1 occurs within the canonical splice donor site of intron 9. It is predicted to cause cryptic donor site activation resulting in an in-frame deletion (removes 19 amino acids) that is expected to remove part of the kinase domain which is critical for protein function. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least three probands meeting a clinical diagnosis of hereditary haemorrhagic telangiectasia (PMID: 15712270, 19508727; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PS4_Moderate

Cardiovascular phenotype Pathogenic:1

Nov 02, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1377+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the ACVRL1 gene. This alteration occurs at the 3' terminus of the ACVRL1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 87 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation was first reported in a patient with liver involvement who met diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) (Kuehl HK, Hum. Mutat. 2005 Mar;25:320). This mutation was later reported in a patient with epistaxis, telangiectasias, gastrointestinal arteriovenous malformations, and a family history of HHT (Sadick H, BMC Med. Genet. 2009 Jun 9;10:53). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
GERP RS		4.9
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs863223406; hg19: chr12-52312900;