rs61739916
Positions:
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_000095.3(COMP):āc.1156A>Gā(p.Asn386Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,613,698 control chromosomes in the GnomAD database, including 1,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.031 ( 104 hom., cov: 31)
Exomes š: 0.046 ( 1706 hom. )
Consequence
COMP
NM_000095.3 missense
NM_000095.3 missense
Scores
5
7
4
Clinical Significance
Conservation
PhyloP100: 7.88
Genes affected
COMP (HGNC:2227): (cartilage oligomeric matrix protein) The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000095.3
BP4
?
Computational evidence support a benign effect (MetaRNN=0.014269739).
BP6
?
Variant 19-18786630-T-C is Benign according to our data. Variant chr19-18786630-T-C is described in ClinVar as [Benign]. Clinvar id is 40987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18786630-T-C is described in Lovd as [Benign]. Variant chr19-18786630-T-C is described in Lovd as [Likely_benign].
BA1
?
GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COMP | NM_000095.3 | c.1156A>G | p.Asn386Asp | missense_variant | 11/19 | ENST00000222271.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COMP | ENST00000222271.7 | c.1156A>G | p.Asn386Asp | missense_variant | 11/19 | 1 | NM_000095.3 | P1 | |
COMP | ENST00000542601.6 | c.1057A>G | p.Asn353Asp | missense_variant | 10/18 | 1 | |||
COMP | ENST00000425807.1 | c.997A>G | p.Asn333Asp | missense_variant | 10/18 | 2 | |||
COMP | ENST00000612179.1 | n.406A>G | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0315 AC: 4794AN: 152076Hom.: 104 Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0329 AC: 8278AN: 251324Hom.: 172 AF XY: 0.0346 AC XY: 4698AN XY: 135876
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GnomAD4 exome AF: 0.0458 AC: 66940AN: 1461504Hom.: 1706 Cov.: 33 AF XY: 0.0457 AC XY: 33217AN XY: 727092
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GnomAD4 genome ? AF: 0.0315 AC: 4789AN: 152194Hom.: 104 Cov.: 31 AF XY: 0.0299 AC XY: 2225AN XY: 74416
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ALSPAC
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222
ESP6500AA
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ESP6500EA
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ExAC
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4099
Asia WGS
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ClinVar
Significance: Benign
Submissions summary: Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Benign:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Multiple epiphyseal dysplasia type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Connective tissue disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 23, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;T
Polyphen
1.0
.;D;.
Vest4
ClinPred
T
GERP RS
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