10-70674918-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_080722.4(ADAMTS14):c.445C>T(p.Arg149Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,613,296 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.72

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019544393).
• BP6: Variant 10-70674918-C-T is Benign according to our data. Variant chr10-70674918-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2640556.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS14	NM_080722.4	c.445C>T	p.Arg149Trp	missense_variant	2/22	ENST00000373207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.445C>T	p.Arg149Trp	missense_variant	2/22	1	NM_080722.4	P4
ADAMTS14	ENST00000373208.5	c.445C>T	p.Arg149Trp	missense_variant	2/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000413 AC: 103 AN: 249636 Hom.: 0 AF XY: 0.000487 AC XY: 66 AN XY: 135476

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000702

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000553 AC: 808 AN: 1460962 Hom.: 1 Cov.: 32 AF XY: 0.000575 AC XY: 418 AN XY: 726800

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000638

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74490

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000560 Hom.: 0

Bravo AF: 0.000344

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

ADAMTS14: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Uncertain	0.97
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.78	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.047
Sift	Benign	0.20	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0050	.;B
Vest4		0.18
MVP		0.42
MPC		0.18
ClinPred		0.0089	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.15
gMVP		0.46

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: rs140711390; hg19: chr10-72434674;