NM_000020.3:c.-5-1855C>T

Variant names:

• chr12-51910615-C-T
• rs11169953
• NM_000020.3:c.-5-1855C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000020.3(ACVRL1):​c.-5-1855C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 151,986 control chromosomes in the GnomAD database, including 10,120 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10120 hom., cov: 32)
• Consequence: ACVRL1 NM_000020.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.738
• Publications: 12 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.-5-1855C>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.-5-1855C>T		intron_variant	Intron 1 of 9	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54191 AN: 151870 Hom.: 10103 Cov.: 32

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.357 AC: 54242 AN: 151986 Hom.: 10120 Cov.: 32 AF XY: 0.356 AC XY: 26452 AN XY: 74270

African (AFR) AF: 0.441 AC: 18288 AN: 41438

American (AMR) AF: 0.287 AC: 4380 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3468

East Asian (EAS) AF: 0.573 AC: 2958 AN: 5158

South Asian (SAS) AF: 0.382 AC: 1841 AN: 4820

European-Finnish (FIN) AF: 0.332 AC: 3506 AN: 10564

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20882 AN: 67954

Other (OTH) AF: 0.364 AC: 767 AN: 2106

Alfa AF: 0.332 Hom.: 16340

Bravo AF: 0.358

Asia WGS AF: 0.476 AC: 1653 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.1
DANN	Benign	0.78
PhyloP100		-0.74
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: rs11169953; hg19: chr12-52304399;