chr12-51920832-G-A

Variant names:

• chr12-51920832-G-A
• rs863223408
• NM_000020.3:c.1451G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1451G>A​(p.Arg484Gln) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249626: Published functional studies demonstrate that variants in residue 484, which is located in the highly conserved NANDOR box region, cause defective signaling with the BMP9 ligand (Ricard et al., 2010)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484G) has been classified as Likely pathogenic. The gene ACVRL1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.99
• Publications: 15 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

Specifications for ACVRL1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249626: Published functional studies demonstrate that variants in residue 484, which is located in the highly conserved NANDOR box region, cause defective signaling with the BMP9 ligand (Ricard et al., 2010).; SCV000822890: Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893).; SCV006079980: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV002701859: Functional studies showed this mutation had no functional activity in response to BMP9, a ligand for ALK1 (Ricard N et al. Blood, 2010 Sep;116:1604-12).
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000020.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51920831-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426037.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 12-51920832-G-A is Pathogenic according to our data. Variant chr12-51920832-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 212796.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.1451G>A	p.Arg484Gln	missense	Exon 10 of 10	NP_000011.2	P37023
	ACVRL1	NM_001077401.2		c.1451G>A	p.Arg484Gln	missense	Exon 9 of 9	NP_001070869.1	A0A0S2Z310
	ACVRL1	NM_001406487.1		c.1451G>A	p.Arg484Gln	missense	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.1451G>A	p.Arg484Gln	missense	Exon 10 of 10	ENSP00000373574.4	P37023
	ACVRL1	ENST00000550683.5	TSL:1	c.1493G>A	p.Arg498Gln	missense	Exon 9 of 9	ENSP00000447884.1	G3V1W8
	ACVRL1	ENST00000551576.6	TSL:1	c.1451G>A	p.Arg484Gln	missense	Exon 11 of 11	ENSP00000455848.2	P37023

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Telangiectasia, hereditary hemorrhagic, type 2 (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Epistaxis;C2973725:Pulmonary arterial hypertension (1)
1	-	-	not provided (1)
1	-	-	not specified (1)
1	-	-	Pulmonary arterial hypertension (1)
1	-	-	Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.73	N
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.91		Loss of MoRF binding (P = 0.0549)
MVP		0.99
MPC		1.7
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.94
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs863223408; hg19: chr12-52314616; COSMIC: COSV101188037; COSMIC: COSV101188037;