chr12-51912002-C-T

Variant names:

• chr12-51912002-C-T
• rs1700159
• NM_000020.3:c.-5-468C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000020.3(ACVRL1):​c.-5-468C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 151,910 control chromosomes in the GnomAD database, including 48,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.80 (48750 hom., cov: 30)
• Consequence: ACVRL1 NM_000020.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 12-51912002-C-T is Benign according to our data. Variant chr12-51912002-C-T is described in ClinVar as [Benign]. Clinvar id is 1271094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.-5-468C>T		intron_variant	Intron 1 of 9	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.-5-468C>T		intron_variant	Intron 1 of 9	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120820 AN: 151792 Hom.: 48701 Cov.: 30

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.780

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.796 AC: 120919 AN: 151910 Hom.: 48750 Cov.: 30 AF XY: 0.793 AC XY: 58904 AN XY: 74248

African (AFR) AF: 0.897 AC: 37182 AN: 41458

American (AMR) AF: 0.621 AC: 9468 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2826 AN: 3470

East Asian (EAS) AF: 0.840 AC: 4318 AN: 5142

South Asian (SAS) AF: 0.844 AC: 4060 AN: 4812

European-Finnish (FIN) AF: 0.789 AC: 8319 AN: 10538

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.768 AC: 52195 AN: 67922

Other (OTH) AF: 0.784 AC: 1655 AN: 2112

Alfa AF: 0.784 Hom.: 81739

Bravo AF: 0.782

Asia WGS AF: 0.863 AC: 3001 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.84
PhyloP100		1.8
PromoterAI		0.39	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1700159; hg19: chr12-52305786;