10-70708654-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_080722.4(ADAMTS14):c.746G>A(p.Arg249Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
ADAMTS14
NM_080722.4 missense
NM_080722.4 missense
Scores
2
12
4
Clinical Significance
Conservation
PhyloP100: 8.13
Genes affected
ADAMTS14 (HGNC:14899): (ADAM metallopeptidase with thrombospondin type 1 motif 14) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme cleaves amino-terminal propeptides from type I procollagen, a necessary step in the formation of collagen fibers. Mutations in this gene may be associated with osteoarthritis in human patients. [provided by RefSeq, May 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAMTS14 | NM_080722.4 | c.746G>A | p.Arg249Gln | missense_variant | 4/22 | ENST00000373207.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAMTS14 | ENST00000373207.2 | c.746G>A | p.Arg249Gln | missense_variant | 4/22 | 1 | NM_080722.4 | P4 | |
ADAMTS14 | ENST00000373208.5 | c.746G>A | p.Arg249Gln | missense_variant | 4/22 | 2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152054Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250868Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135744
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461568Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727068
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152172Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74396
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | The c.746G>A (p.R249Q) alteration is located in exon 4 (coding exon 4) of the ADAMTS14 gene. This alteration results from a G to A substitution at nucleotide position 746, causing the arginine (R) at amino acid position 249 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
0.99
.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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