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NM_000020.3(ACVRL1):c.1377+4A>T AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Mar 15, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001287259.10

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1377+4A>T]

NM_000020.3(ACVRL1):c.1377+4A>T

Gene:
ACVRL1:activin A receptor like type 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q13.13
Genomic location:
Preferred name:
NM_000020.3(ACVRL1):c.1377+4A>T
HGVS:
  • NC_000012.12:g.51919119A>T
  • NG_009549.1:g.16702A>T
  • NM_000020.3:c.1377+4A>TMANE SELECT
  • NM_001077401.2:c.1377+4A>T
  • LRG_543:g.16702A>T
  • NC_000012.11:g.52312903A>T
Links:
dbSNP: rs1940909579
NCBI 1000 Genomes Browser:
rs1940909579
Molecular consequence:
  • NM_000020.3:c.1377+4A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001077401.2:c.1377+4A>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Telangiectasia, hereditary hemorrhagic, type 2 (HHT2)
Synonyms:
Telangiectasia, hereditary hemorrhagic, type II; Osler Weber Rendu syndrome type 2
Identifiers:
MONDO: MONDO:0010880; MedGen: C1838163; Orphanet: 774; OMIM: 600376

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001473930ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)		Uncertain significance
(Oct 8, 2021) 		germlineclinical testing

Citation Link,

SCV004805896ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen HHT ACMG Specifications ACVRL1 V1.1.0)		Uncertain Significance
(Mar 15, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473930.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ACVRL1 c.1377+4A>T variant, to our knowledge, is not reported in the medical literature but is listed in the ClinVar database (Variation ID: 994236). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.1377+4A>T variant is uncertain at this time.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen, SCV004805896.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000020.3: c.1377+4A>T variant in ACVRL1 is an intronic variant located in intron 9. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.39 for donor loss, predicting that the variant disrupts the donor splice site of intron 9 of ACVRL1 (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, PP3 (specification version 1.0.0; 1/04/2024).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 6, 2024