NM_000020.3:c.-5-227C>G

Variant names:

• chr12-51912243-C-G
• rs2277381
• NM_000020.3:c.-5-227C>G

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.144
• Publications: 3 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 -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 rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.-5-227C>G		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.-5-227C>G		intron_variant	Intron 1 of 9	1	NM_000020.3	ENSP00000373574.4

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

African (AFR) AF: 0.0248 AC: 327 AN: 13174

American (AMR) AF: 0.0508 AC: 1158 AN: 22788

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 2227 AN: 14596

East Asian (EAS) AF: 0.312 AC: 9864 AN: 31586

South Asian (SAS) AF: 0.156 AC: 7481 AN: 47946

European-Finnish (FIN) AF: 0.118 AC: 3613 AN: 30712

Middle Eastern (MID) AF: 0.0898 AC: 184 AN: 2050

European-Non Finnish (NFE) AF: 0.113 AC: 32004 AN: 282262

Other (OTH) AF: 0.127 AC: 3417 AN: 27002

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

African (AFR) AF: 0.0245 AC: 1016 AN: 41540

American (AMR) AF: 0.0651 AC: 996 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3470

East Asian (EAS) AF: 0.354 AC: 1827 AN: 5154

South Asian (SAS) AF: 0.160 AC: 774 AN: 4826

European-Finnish (FIN) AF: 0.113 AC: 1194 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7493 AN: 67998

Other (OTH) AF: 0.100 AC: 212 AN: 2110

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		-0.14
PromoterAI		-0.15	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: rs2277381; hg19: chr12-52306027;