10-70674604-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080722.4(ADAMTS14):c.131G>A(p.Cys44Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 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: 1.60

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27701318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS14	NM_080722.4	c.131G>A	p.Cys44Tyr	missense_variant	2/22	ENST00000373207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.131G>A	p.Cys44Tyr	missense_variant	2/22	1	NM_080722.4	P4
ADAMTS14	ENST00000373208.5	c.131G>A	p.Cys44Tyr	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

May 31, 2023

The c.131G>A (p.C44Y) alteration is located in exon 2 (coding exon 2) of the ADAMTS14 gene. This alteration results from a G to A substitution at nucleotide position 131, causing the cysteine (C) at amino acid position 44 to be replaced by a tyrosine (Y). 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	0.096
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.55	N;N
REVEL	Benign	0.059
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.15	.;B
Vest4		0.34
MutPred		0.42		Loss of catalytic residue at P43 (P = 0.0062);Loss of catalytic residue at P43 (P = 0.0062);
MVP		0.63
MPC		0.50
ClinPred		0.48	T
GERP RS		1.4
Varity_R		0.43
gMVP		0.82

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: rs990843726; hg19: chr10-72434360;