chr3-33114523-A-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2
The NM_006371.5(CRTAP):āc.446A>Gā(p.Lys149Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,602,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. K149K) has been classified as Likely benign.
Frequency
Consequence
NM_006371.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRTAP | NM_006371.5 | c.446A>G | p.Lys149Arg | missense_variant | 1/7 | ENST00000320954.11 | |
CRTAP | NM_001393363.1 | c.446A>G | p.Lys149Arg | missense_variant | 1/6 | ||
CRTAP | NM_001393364.1 | c.446A>G | p.Lys149Arg | missense_variant | 1/6 | ||
CRTAP | NM_001393365.1 | c.446A>G | p.Lys149Arg | missense_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRTAP | ENST00000320954.11 | c.446A>G | p.Lys149Arg | missense_variant | 1/7 | 1 | NM_006371.5 | P1 | |
CRTAP | ENST00000449224.1 | c.446A>G | p.Lys149Arg | missense_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000762 AC: 116AN: 152142Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000719 AC: 156AN: 216928Hom.: 0 AF XY: 0.000758 AC XY: 91AN XY: 120002
GnomAD4 exome AF: 0.00111 AC: 1612AN: 1450680Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 849AN XY: 720828
GnomAD4 genome AF: 0.000762 AC: 116AN: 152256Hom.: 0 Cov.: 34 AF XY: 0.000618 AC XY: 46AN XY: 74428
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Osteogenesis imperfecta type 7 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 149 of the CRTAP protein (p.Lys149Arg). This variant is present in population databases (rs201564256, 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: 344807). 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 not 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 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at