rs1057517944

Variant names:

• chr12-51920816-C-T
• rs1057517944
• NM_000020.3:c.1435C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-51920816-C-T
• chr12-51920816-C-A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1435C>T​(p.Arg479*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000602411: "functional analyses of the variant protein demonstrate a loss of ligand-induced receptor signaling and down-regulation of the protein (Garamszeg 2001)."".

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.537
• Publications: 13 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, ClinGen, Labcorp Genetics (formerly Invitae), 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 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000602411: "functional analyses of the variant protein demonstrate a loss of ligand-induced receptor signaling and down-regulation of the protein (Garamszeg 2001)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51920816-C-T is Pathogenic according to our data. Variant chr12-51920816-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 372722.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	NM_000020.3	MANE Select	c.1435C>T	p.Arg479*	stop_gained	Exon 10 of 10	NP_000011.2	P37023
	ACVRL1	NM_001077401.2		c.1435C>T	p.Arg479*	stop_gained	Exon 9 of 9	NP_001070869.1	A0A0S2Z310
	ACVRL1	NM_001406487.1		c.1435C>T	p.Arg479*	stop_gained	Exon 11 of 11	NP_001393416.1	A0A0S2Z310

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.1435C>T	p.Arg479*	stop_gained	Exon 10 of 10	ENSP00000373574.4	P37023
	ACVRL1	ENST00000550683.5	TSL:1	c.1477C>T	p.Arg493*	stop_gained	Exon 9 of 9	ENSP00000447884.1	G3V1W8
	ACVRL1	ENST00000551576.6	TSL:1	c.1435C>T	p.Arg479*	stop_gained	Exon 11 of 11	ENSP00000455848.2	P37023

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251420 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461804 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727204

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

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: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Telangiectasia, hereditary hemorrhagic, type 2 (5)
3	-	-	not provided (3)
2	-	-	Hereditary hemorrhagic telangiectasia (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.53	D
PhyloP100		0.54
Vest4		0.84
GERP RS		4.4
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057517944; hg19: chr12-52314600;