rs4747096

Positions:

• chr10-70758253-A-G
• chr10-70758253-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000373207.2(ADAMTS14):​c.3146A>G​(p.Glu1049Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,613,734 control chromosomes in the GnomAD database, including 27,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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. E1049D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (2801 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24808 hom.)
• Consequence: ADAMTS14 ENST00000373207.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004669875).
• BP6: Variant 10-70758253-A-G is Benign according to our data. Variant chr10-70758253-A-G is described in ClinVar as [Benign]. Clinvar id is 1287457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS14	NM_080722.4	c.3146A>G	p.Glu1049Gly	missense_variant	21/22	ENST00000373207.2	NP_542453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.3146A>G	p.Glu1049Gly	missense_variant	21/22	1	NM_080722.4	ENSP00000362303	P4
ADAMTS14	ENST00000373208.5	c.3155A>G	p.Glu1052Gly	missense_variant	21/22	2		ENSP00000362304	A2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28622 AN: 152084 Hom.: 2803 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.192 AC: 48305 AN: 251106 Hom.: 5095 AF XY: 0.188 AC XY: 25532 AN XY: 135716

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.352

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.179 AC: 262019 AN: 1461532 Hom.: 24808 Cov.: 36 AF XY: 0.178 AC XY: 129417 AN XY: 727068

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.188 AC: 28622 AN: 152202 Hom.: 2801 Cov.: 33 AF XY: 0.191 AC XY: 14213 AN XY: 74418

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.180

Alfa AF: 0.170 Hom.: 5193

Bravo AF: 0.187

TwinsUK AF: 0.166 AC: 617

ALSPAC AF: 0.173 AC: 665

ESP6500AA AF: 0.188 AC: 830

ESP6500EA AF: 0.161 AC: 1387

ExAC AF: 0.189 AC: 22882

Asia WGS AF: 0.268 AC: 934 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 23491141) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.8
DANN	Benign	0.32
DEOGEN2	Benign	0.0085	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.059	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.7	.;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.49	N;N
REVEL	Benign	0.059
Sift	Benign	0.67	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	.;B
Vest4		0.028
MPC		0.20
ClinPred		0.0012	T
GERP RS		3.0
Varity_R		0.029
gMVP		0.38

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: rs4747096; hg19: chr10-72518009; COSMIC: COSV64602021;