10-70753879-C-A

Variant names:

• chr10-70753879-C-A
• rs12774070
• NM_080722.4:c.2809C>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ADAMTS14	NM_080722.4	c.2809C>A	p.Leu937Met	missense_variant	Exon 19 of 22	ENST00000373207.2	NP_542453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.2809C>A	p.Leu937Met	missense_variant	Exon 19 of 22	1	NM_080722.4	ENSP00000362303.1
ADAMTS14	ENST00000373208.5	c.2818C>A	p.Leu940Met	missense_variant	Exon 19 of 22	2		ENSP00000362304.1

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

GnomAD2 exomes AF: 0.228 AC: 47791 AN: 209372 AF XY: 0.235

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 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

African (AFR) AF: 0.0442 AC: 1473 AN: 33340

American (AMR) AF: 0.176 AC: 7171 AN: 40786

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5235 AN: 25552

East Asian (EAS) AF: 0.161 AC: 6258 AN: 38904

South Asian (SAS) AF: 0.225 AC: 18476 AN: 81970

European-Finnish (FIN) AF: 0.256 AC: 13103 AN: 51180

Middle Eastern (MID) AF: 0.244 AC: 1396 AN: 5730

European-Non Finnish (NFE) AF: 0.275 AC: 303390 AN: 1101846

Other (OTH) AF: 0.236 AC: 14084 AN: 59638

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

African (AFR) AF: 0.0510 AC: 2122 AN: 41568

American (AMR) AF: 0.205 AC: 3135 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 726 AN: 3470

East Asian (EAS) AF: 0.162 AC: 835 AN: 5166

South Asian (SAS) AF: 0.216 AC: 1046 AN: 4832

European-Finnish (FIN) AF: 0.262 AC: 2784 AN: 10608

Middle Eastern (MID) AF: 0.252 AC: 73 AN: 290

European-Non Finnish (NFE) AF: 0.272 AC: 18462 AN: 67972

Other (OTH) AF: 0.207 AC: 438 AN: 2112

Alfa AF: 0.214 Hom.: 3544

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
PhyloP100		5.1
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12774070; hg19: chr10-72513635; COSMIC: COSV64599396;