NM_000020.3:c.772G>A

Variant names:

• chr12-51914585-G-A
• rs1555152966
• NM_000020.3:c.772G>A
• ACVRL1 p.Gly258Ser

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.772G>A​(p.Gly258Ser) variant causes a missense, splice region 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G258G) has been classified as Uncertain significance. The gene ACVRL1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 NM_000020.3 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.73
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000020.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.903
• PP5: Variant 12-51914585-G-A is Pathogenic according to our data. Variant chr12-51914585-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 444101.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.772G>A	p.Gly258Ser	missense splice_region	Exon 6 of 10	NP_000011.2	P37023
	ACVRL1	NM_001077401.2		c.772G>A	p.Gly258Ser	missense splice_region	Exon 5 of 9	NP_001070869.1	A0A0S2Z310
	ACVRL1	NM_001406487.1		c.772G>A	p.Gly258Ser	missense splice_region	Exon 7 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.772G>A	p.Gly258Ser	missense splice_region	Exon 6 of 10	ENSP00000373574.4	P37023
	ACVRL1	ENST00000550683.5	TSL:1	c.814G>A	p.Gly272Ser	missense splice_region	Exon 5 of 9	ENSP00000447884.1	G3V1W8
	ACVRL1	ENST00000551576.6	TSL:1	c.772G>A	p.Gly258Ser	missense splice_region	Exon 7 of 11	ENSP00000455848.2	P37023

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hereditary hemorrhagic telangiectasia (1)
1	-	-	Telangiectasia, hereditary hemorrhagic, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.69	N
PhyloP100		9.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.032	D
Varity_R		0.83
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555152966;

hg19: chr12-52308369;