10-70702415-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080722.4(ADAMTS14):c.626G>A(p.Arg209Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000968 in 1,613,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08757821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS14	NM_080722.4	c.626G>A	p.Arg209Gln	missense_variant	3/22	ENST00000373207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.626G>A	p.Arg209Gln	missense_variant	3/22	1	NM_080722.4	P4
ADAMTS14	ENST00000373208.5	c.626G>A	p.Arg209Gln	missense_variant	3/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000831 AC: 208 AN: 250442 Hom.: 0 AF XY: 0.000746 AC XY: 101 AN XY: 135346

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000988 AC: 1444 AN: 1461544 Hom.: 1 Cov.: 30 AF XY: 0.000961 AC XY: 699 AN XY: 727076

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74478

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000854

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000873 AC: 106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.626G>A (p.R209Q) alteration is located in exon 3 (coding exon 3) of the ADAMTS14 gene. This alteration results from a G to A substitution at nucleotide position 626, causing the arginine (R) at amino acid position 209 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	.;D
Vest4		0.75
MVP		0.84
MPC		0.73
ClinPred		0.057	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141259412; hg19: chr10-72462171;