12-51913390-G-C

Variant names:

• chr12-51913390-G-C
• rs376033978
• NM_000020.3:c.313+40G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000020.3(ACVRL1):​c.313+40G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,605,376 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: ACVRL1 NM_000020.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.273
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-51913390-G-C is Benign according to our data. Variant chr12-51913390-G-C is described in ClinVar as [Benign]. Clinvar id is 416700.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000781 (119/152280) while in subpopulation NFE AF = 0.0014 (95/68016). AF 95% confidence interval is 0.00117. There are 1 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.313+40G>C		intron_variant	Intron 3 of 9	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.313+40G>C		intron_variant	Intron 3 of 9	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152162 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000576 AC: 133 AN: 231046 AF XY: 0.000548

Gnomad AFR exome AF: 0.0000715

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000691

GnomAD4 exome AF: 0.00126 AC: 1828 AN: 1453096 Hom.: 1 Cov.: 41 AF XY: 0.00124 AC XY: 899 AN XY: 722148

African (AFR) AF: 0.000150 AC: 5 AN: 33282

American (AMR) AF: 0.000364 AC: 16 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.00 AC: 0 AN: 84776

European-Finnish (FIN) AF: 0.0000392 AC: 2 AN: 51040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00156 AC: 1728 AN: 1108756

Other (OTH) AF: 0.00128 AC: 77 AN: 60122

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152280 Hom.: 1 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74448

African (AFR) AF: 0.000409 AC: 17 AN: 41560

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.000669

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.46
DANN	Benign	0.69
PhyloP100		-0.27
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: rs376033978; hg19: chr12-52307174;