rs12774070

Positions:

• chr10-70753879-C-A
• chr10-70753879-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080722.4(ADAMTS14):​c.2809C>A​(p.Leu937Met) variant causes a missense change. The variant allele was found at a frequency of 0.252 in 1,591,176 control chromosomes in the GnomAD database, including 52,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L937P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3602 hom., cov: 34)
  • Exomes 𝑓: 0.26 (49303 hom.)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.06

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016207993).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS14	NM_080722.4	c.2809C>A	p.Leu937Met	missense_variant	19/22	ENST00000373207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.2809C>A	p.Leu937Met	missense_variant	19/22	1	NM_080722.4	P4
ADAMTS14	ENST00000373208.5	c.2818C>A	p.Leu940Met	missense_variant	19/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29907 AN: 152112 Hom.: 3607 Cov.: 34

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.208

GnomAD3 exomes AF: 0.228 AC: 47791 AN: 209372 Hom.: 5849 AF XY: 0.235 AC XY: 26413 AN XY: 112402

Gnomad AFR exome AF: 0.0486

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.159

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.258 AC: 370586 AN: 1438946 Hom.: 49303 Cov.: 41 AF XY: 0.257 AC XY: 183553 AN XY: 713096

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.236

GnomAD4 genome AF: 0.196 AC: 29887 AN: 152230 Hom.: 3602 Cov.: 34 AF XY: 0.196 AC XY: 14620 AN XY: 74428

Gnomad4 AFR AF: 0.0510

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.207

Alfa AF: 0.236 Hom.: 2235

Bravo AF: 0.186

TwinsUK AF: 0.270 AC: 1003

ALSPAC AF: 0.287 AC: 1105

ESP6500AA AF: 0.0602 AC: 265

ESP6500EA AF: 0.264 AC: 2270

ExAC AF: 0.208 AC: 24994

Asia WGS AF: 0.180 AC: 625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L
MutationTaster	Benign	0.33	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.17	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	.;D
Vest4		0.13
MPC		0.64
ClinPred		0.012	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12774070; hg19: chr10-72513635; COSMIC: COSV64599396;