12-51912243-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000020.3(ACVRL1):c.-5-227C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 624,328 control chromosomes in the GnomAD database, including 5,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (993 hom., cov: 32)
  • Exomes 𝑓: 0.13 (4728 hom.)
• Consequence: ACVRL1 NM_000020.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.144

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-51912243-C-G is Benign according to our data. Variant chr12-51912243-C-G is described in ClinVar as [Benign]. Clinvar id is 810906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.-5-227C>G		intron_variant		ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.-5-227C>G		intron_variant		1	NM_000020.3	P1
ACVRL1	ENST00000551576.6	c.-5-227C>G		intron_variant		1		P1
ACVRL1	ENST00000552678.2	c.-5-227C>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 14147 AN: 152094 Hom.: 992 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0953

GnomAD4 exome AF: 0.128 AC: 60275 AN: 472116 Hom.: 4728 AF XY: 0.130 AC XY: 32659 AN XY: 251360

Gnomad4 AFR exome AF: 0.0248

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.0929 AC: 14146 AN: 152212 Hom.: 993 Cov.: 32 AF XY: 0.0941 AC XY: 7004 AN XY: 74418

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.0651

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.100

Alfa AF: 0.100 Hom.: 103

Bravo AF: 0.0862

Asia WGS AF: 0.229 AC: 794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 22, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.9
Dann	Benign	0.69

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: rs2277381; hg19: chr12-52306027;