rs1555152518

Positions:

• chr12-51913299-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The ENST00000388922.9(ACVRL1):​c.262T>G​(p.Tyr88Asp) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y88C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVRL1 ENST00000388922.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.773

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000388922.9
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3614061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.262T>G	p.Tyr88Asp	missense_variant	3/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.262T>G	p.Tyr88Asp	missense_variant	3/10	1	NM_000020.3	ENSP00000373574	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Nov 27, 2023

PP2, PM2 -

Lip telangiectasia;C3809715:Spontaneous, recurrent epistaxis;C4022018:Telangiectasia of the skin;C4025877:Oral cavity telangiectasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.24	.;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.90	.;L;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.1	D;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.015	D;T;D;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.022	.;B;.;.
Vest4		0.50, 0.53
MutPred		0.64		Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;.;
MVP		0.89
MPC		1.1
ClinPred		0.19	T
GERP RS		2.1
Varity_R		0.20
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555152518; hg19: chr12-52307083;