chr3-33114528-C-G
Position:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BS1_SupportingBS2
The NM_006371.5(CRTAP):āc.451C>Gā(p.Leu151Val) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,602,454 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L151P) has been classified as Likely pathogenic.
Frequency
Genomes: š 0.00069 ( 1 hom., cov: 34)
Exomes š: 0.0013 ( 5 hom. )
Consequence
CRTAP
NM_006371.5 missense
NM_006371.5 missense
Scores
4
12
3
Clinical Significance
Conservation
PhyloP100: 3.79
Genes affected
CRTAP (HGNC:2379): (cartilage associated protein) The protein encoded by this gene is similar to the chicken and mouse CRTAP genes. The encoded protein is a scaffolding protein that may influence the activity of at least one member of the cytohesin/ARNO family in response to specific cellular stimuli. Defects in this gene are associated with osteogenesis imperfecta, a connective tissue disorder characterized by bone fragility and low bone mass. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-33114529-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1510318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000689 (105/152358) while in subpopulation NFE AF= 0.00123 (84/68032). AF 95% confidence interval is 0.00102. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRTAP | NM_006371.5 | c.451C>G | p.Leu151Val | missense_variant | 1/7 | ENST00000320954.11 | |
CRTAP | NM_001393363.1 | c.451C>G | p.Leu151Val | missense_variant | 1/6 | ||
CRTAP | NM_001393364.1 | c.451C>G | p.Leu151Val | missense_variant | 1/6 | ||
CRTAP | NM_001393365.1 | c.451C>G | p.Leu151Val | missense_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRTAP | ENST00000320954.11 | c.451C>G | p.Leu151Val | missense_variant | 1/7 | 1 | NM_006371.5 | P1 | |
CRTAP | ENST00000449224.1 | c.451C>G | p.Leu151Val | missense_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000690 AC: 105AN: 152244Hom.: 1 Cov.: 34
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GnomAD3 exomes AF: 0.000529 AC: 114AN: 215494Hom.: 0 AF XY: 0.000504 AC XY: 60AN XY: 119164
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GnomAD4 exome AF: 0.00130 AC: 1890AN: 1450096Hom.: 5 Cov.: 32 AF XY: 0.00123 AC XY: 883AN XY: 720512
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GnomAD4 genome AF: 0.000689 AC: 105AN: 152358Hom.: 1 Cov.: 34 AF XY: 0.000685 AC XY: 51AN XY: 74502
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 7 Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 151 of the CRTAP protein (p.Leu151Val). This variant is present in population databases (rs202118861, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 429858). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRTAP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 11, 2019 | The CRTAP c.451C>G; p.Leu151Val variant (rs202118861), to our knowledge, has not been described in the medical literature but is listed as a variant of uncertain significance in ClinVar (Variation ID: 429858). It is observed in the general population at an overall frequency of 0.053% (131/246878 alleles) in the Genome Aggregation Database. The leucine at codon 151 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Another variant at this codon position (c.452T>C; p.Leu151Pro) has been described homozygously in an individual affected with osteogenesis imperfect type 3, though it is unclear if this variant was causative for the phenotype in this patient (Caparros-Martin 2016). Due to limited information regarding the p.Leu151Val variant, its clinical significance cannot be determined with certainty. REFERENCES Caparros-Martin J et al. Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta. Mol Genet Genomic Med. 2016 Dec 20;5(1):28-39. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Osteogenesis imperfecta Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at