chr12-51914374-TG-T

Variant names:

• chr12-51914374-TG-T
• rs864622702
• NM_000020.3:c.626-59delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000020.3(ACVRL1):​c.626-59delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,608,886 control chromosomes in the GnomAD database, including 258 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 33)
  • Exomes 𝑓: 0.018 (246 hom.)
• Consequence: ACVRL1 NM_000020.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 12-51914374-TG-T is Benign according to our data. Variant chr12-51914374-TG-T is described in ClinVar as [Likely_benign]. Clinvar id is 220940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1725/152226) while in subpopulation NFE AF = 0.0189 (1284/67980). AF 95% confidence interval is 0.018. There are 12 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.626-59delG		intron_variant	Intron 5 of 9	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.626-64delG		intron_variant	Intron 5 of 9	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1726 AN: 152108 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.0177 AC: 25733 AN: 1456660 Hom.: 246 AF XY: 0.0172 AC XY: 12436 AN XY: 724730

African (AFR) AF: 0.00261 AC: 87 AN: 33346

American (AMR) AF: 0.00718 AC: 320 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 678 AN: 26064

East Asian (EAS) AF: 0.00212 AC: 84 AN: 39664

South Asian (SAS) AF: 0.00355 AC: 305 AN: 85854

European-Finnish (FIN) AF: 0.00602 AC: 321 AN: 53358

Middle Eastern (MID) AF: 0.00475 AC: 24 AN: 5056

European-Non Finnish (NFE) AF: 0.0207 AC: 22910 AN: 1108552

Other (OTH) AF: 0.0167 AC: 1004 AN: 60190

GnomAD4 genome AF: 0.0113 AC: 1725 AN: 152226 Hom.: 12 Cov.: 33 AF XY: 0.0101 AC XY: 750 AN XY: 74432

African (AFR) AF: 0.00330 AC: 137 AN: 41552

American (AMR) AF: 0.00752 AC: 115 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3470

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1284 AN: 67980

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0154 Hom.: 2

Bravo AF: 0.0119

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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: rs864622702; hg19: chr12-52308158;