chr3-33124427-T-C
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006371.5(CRTAP):āc.641T>Cā(p.Val214Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00311 in 1,614,160 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0022 ( 7 hom., cov: 33)
Exomes š: 0.0032 ( 125 hom. )
Consequence
CRTAP
NM_006371.5 missense
NM_006371.5 missense
Scores
6
8
4
Clinical Significance
Conservation
PhyloP100: 6.15
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0097948015).
BP6
Variant 3-33124427-T-C is Benign according to our data. Variant chr3-33124427-T-C is described in ClinVar as [Benign]. Clinvar id is 284535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33124427-T-C is described in Lovd as [Likely_benign]. Variant chr3-33124427-T-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00218 (332/152308) while in subpopulation SAS AF= 0.0491 (237/4826). AF 95% confidence interval is 0.044. There are 7 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRTAP | NM_006371.5 | c.641T>C | p.Val214Ala | missense_variant | 3/7 | ENST00000320954.11 | |
CRTAP | NM_001393363.1 | c.641T>C | p.Val214Ala | missense_variant | 3/6 | ||
CRTAP | NM_001393364.1 | c.641T>C | p.Val214Ala | missense_variant | 3/6 | ||
CRTAP | NM_001393365.1 | c.491T>C | p.Val164Ala | missense_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRTAP | ENST00000320954.11 | c.641T>C | p.Val214Ala | missense_variant | 3/7 | 1 | NM_006371.5 | P1 | |
CRTAP | ENST00000449224.1 | c.641T>C | p.Val214Ala | missense_variant | 3/6 | 2 | |||
CRTAP | ENST00000485310.1 | n.235T>C | non_coding_transcript_exon_variant | 3/5 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00217 AC: 331AN: 152190Hom.: 7 Cov.: 33
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GnomAD3 exomes AF: 0.00613 AC: 1541AN: 251484Hom.: 42 AF XY: 0.00796 AC XY: 1082AN XY: 135918
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GnomAD4 exome AF: 0.00320 AC: 4683AN: 1461852Hom.: 125 Cov.: 31 AF XY: 0.00438 AC XY: 3185AN XY: 727224
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GnomAD4 genome AF: 0.00218 AC: 332AN: 152308Hom.: 7 Cov.: 33 AF XY: 0.00290 AC XY: 216AN XY: 74488
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 13, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Osteogenesis imperfecta type 7 Benign:2
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Osteogenesis imperfecta Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 25, 2022 | - - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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