rs758683062

Variant names:

• chr12-51913675-C-T
• rs758683062
• NM_000020.3:c.430C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-51913675-C-T
• chr12-51913675-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.430C>T​(p.Arg144*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,930 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.959
• Publications: 12 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51913675-C-T is Pathogenic according to our data. Variant chr12-51913675-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 212804.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.430C>T	p.Arg144*	stop_gained	Exon 4 of 10	NP_000011.2	P37023
	ACVRL1	NM_001077401.2		c.430C>T	p.Arg144*	stop_gained	Exon 3 of 9	NP_001070869.1	A0A0S2Z310
	ACVRL1	NM_001406487.1		c.430C>T	p.Arg144*	stop_gained	Exon 5 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.430C>T	p.Arg144*	stop_gained	Exon 4 of 10	ENSP00000373574.4	P37023
	ACVRL1	ENST00000550683.5	TSL:1	c.472C>T	p.Arg158*	stop_gained	Exon 3 of 9	ENSP00000447884.1	G3V1W8
	ACVRL1	ENST00000551576.6	TSL:1	c.430C>T	p.Arg144*	stop_gained	Exon 5 of 11	ENSP00000455848.2	P37023

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246414 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457930 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725480

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Telangiectasia, hereditary hemorrhagic, type 2 (4)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Benign	0.60	D
PhyloP100		0.96
Vest4		0.91
GERP RS		4.7
Mutation Taster		=3/197	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: rs758683062; hg19: chr12-52307459; COSMIC: COSV66360278; COSMIC: COSV66360278;