rs1085307406

Variant names:

• chr12-51913330-A-G
• rs1085307406
• NM_000020.3:c.293A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000020.3(ACVRL1):​c.293A>G​(p.Asn98Ser) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N98N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.15
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 12-51913330-A-G is Pathogenic according to our data. Variant chr12-51913330-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426011.

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.293A>G	p.Asn98Ser	missense	Exon 3 of 10	NP_000011.2
	ACVRL1	NM_001077401.2		c.293A>G	p.Asn98Ser	missense	Exon 2 of 9	NP_001070869.1
	ACVRL1	NM_001406487.1		c.293A>G	p.Asn98Ser	missense	Exon 4 of 11	NP_001393416.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.293A>G	p.Asn98Ser	missense	Exon 3 of 10	ENSP00000373574.4
	ACVRL1	ENST00000550683.5	TSL:1	c.335A>G	p.Asn112Ser	missense	Exon 2 of 9	ENSP00000447884.1
	ACVRL1	ENST00000551576.6	TSL:1	c.293A>G	p.Asn98Ser	missense	Exon 4 of 11	ENSP00000455848.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
1	-	-	Pulmonary hypertension, primary, 1 (1)
1	-	-	Telangiectasia, hereditary hemorrhagic, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.51
Sift	Benign	0.064	T
Sift4G	Benign	0.14	T
Polyphen		0.91	P
Vest4		0.52
MutPred		0.86		Gain of disorder (P = 0.0906)
MVP		0.94
MPC		0.99
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.34
gMVP		0.85
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307406; hg19: chr12-52307114;