10-70674865-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080722.4(ADAMTS14):c.392G>T(p.Gly131Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS14	NM_080722.4	c.392G>T	p.Gly131Val	missense_variant	2/22	ENST00000373207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.392G>T	p.Gly131Val	missense_variant	2/22	1	NM_080722.4	P4
ADAMTS14	ENST00000373208.5	c.392G>T	p.Gly131Val	missense_variant	2/22	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jan 10, 2023

The c.392G>T (p.G131V) alteration is located in exon 2 (coding exon 2) of the ADAMTS14 gene. This alteration results from a G to T substitution at nucleotide position 392, causing the glycine (G) at amino acid position 131 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.99	.;D
Vest4		0.87
MutPred		0.75		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.71
MPC		0.78
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.90
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-72434621;