chr12-51915421-A-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000020.3(ACVRL1):​c.969A>C​(p.Lys323Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K323E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ACVRL1
NM_000020.3 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.167

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000020.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-51915419-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1767756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACVRL1NM_000020.3 linkc.969A>C p.Lys323Asn missense_variant Exon 7 of 10 ENST00000388922.9 NP_000011.2 P37023A0A0S2Z310

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACVRL1ENST00000388922.9 linkc.969A>C p.Lys323Asn missense_variant Exon 7 of 10 1 NM_000020.3 ENSP00000373574.4 P37023

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.000359
AC:
89
AN:
248192
AF XY:
0.000274
show subpopulations
Gnomad AFR exome
AF:
0.00140
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00122
Gnomad FIN exome
AF:
0.000469
Gnomad NFE exome
AF:
0.000259
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000397
AC:
58
AN:
1460694
Hom.:
0
Cov.:
32
AF XY:
0.0000482
AC XY:
35
AN XY:
726698
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.000857
AC:
45
AN:
52518
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5668
European-Non Finnish (NFE)
AF:
0.00000719
AC:
8
AN:
1111930
Other (OTH)
AF:
0.0000829
AC:
5
AN:
60306
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.315
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.000824
AC:
100

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Uncertain:1
Apr 25, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces lysine with asparagine at codon 323 of the ACVRL1 protein (p.Lys323Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. The frequency data for this variant (rs771877309) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a ACVRL1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.;T
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.51
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Uncertain
0.68
D;D;D
MetaSVM
Uncertain
0.67
D
MutationAssessor
Benign
1.9
L;.;.
PhyloP100
-0.17
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.0
D;D;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.72
MutPred
0.79
Loss of methylation at K323 (P = 0.0204);.;.;
MVP
0.95
MPC
1.7
ClinPred
0.12
T
GERP RS
-6.3
PromoterAI
-0.0055
Neutral
Varity_R
0.99
gMVP
0.91
Mutation Taster
=13/87
disease causing

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

Other links and lift over

dbSNP: rs771877309; hg19: chr12-52309205; API