12-51913187-G-T

Position:

• chr12-51913187-G-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.150G>T​(p.Trp50Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,444,186 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W50R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_000020.3 (ACVRL1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1459447
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr12-51913185-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACVRL1. . Gene score misZ 2.4458 (greater than the threshold 3.09). Trascript score misZ 3.182 (greater than threshold 3.09). GenCC has associacion of gene with hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 12-51913187-G-T is Pathogenic according to our data. Variant chr12-51913187-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.150G>T	p.Trp50Cys	missense_variant	3/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.150G>T	p.Trp50Cys	missense_variant	3/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444186 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 716940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 27, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 10187774, 14684682). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. ClinVar contains an entry for this variant (Variation ID: 8246). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 9245985, 12843319; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 50 of the ACVRL1 protein (p.Trp50Cys). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2023

Segregates with disease in affected individuals from a single family in the published literature (Abdalla et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate mis-localization and impaired protein activity (Lux et al., 1999; Harrison et al., 2003); This variant is associated with the following publications: (PMID: 16611099, 22028876, 9245985, 10187774, 14684682, 12843319, 10694922, 10767348, 17576210, 22718755, 15266205) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The p.W50C pathogenic mutation (also known as c.150G>T), located in coding exon 2 of the ACVRL1 gene, results from a G to T substitution at nucleotide position 150. The tryptophan at codon 50 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Berg JN et al. Am J Hum Genet, 1997 Jul;61:60-7; Abdalla SA et al. J Med Genet, 2003 Jul;40:494-502). In vitro studies showed that this alteration results in low signaling activity probably due abnormal cellular localization (Lux A et al. J Biol Chem, 1999 Apr;274:9984-92; Harrison RE et al. J Med Genet, 2003 Dec;40:865-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;T;D;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.7	.;L;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-11	D;N;N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;T;D;T
Sift4G	Pathogenic	0.0	D;T;D;T
Polyphen		0.96	.;D;.;.
Vest4		0.66, 0.88
MutPred		0.93		Gain of disorder (P = 0.0331);Gain of disorder (P = 0.0331);.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.43
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909285; hg19: chr12-52306971;