10-70672857-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080722.4(ADAMTS14):c.55T>A(p.Cys19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,505,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.133

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105924815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS14	NM_080722.4	c.55T>A	p.Cys19Ser	missense_variant	1/22	ENST00000373207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.55T>A	p.Cys19Ser	missense_variant	1/22	1	NM_080722.4	P4
ADAMTS14	ENST00000373208.5	c.55T>A	p.Cys19Ser	missense_variant	1/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000209 AC: 21 AN: 100300 Hom.: 0 AF XY: 0.000213 AC XY: 12 AN XY: 56326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000349

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000485 AC: 656 AN: 1353692 Hom.: 0 Cov.: 33 AF XY: 0.000452 AC XY: 302 AN XY: 668156

Gnomad4 AFR exome AF: 0.0000364

Gnomad4 AMR exome AF: 0.000575

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.000445

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.000118 AC: 10

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

Oct 03, 2022

The c.55T>A (p.C19S) alteration is located in exon 1 (coding exon 1) of the ADAMTS14 gene. This alteration results from a T to A substitution at nucleotide position 55, causing the cysteine (C) at amino acid position 19 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	15
Dann	Benign	0.89
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.055
Sift	Benign	0.13	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.020	.;B
Vest4		0.42
MutPred		0.66		Gain of disorder (P = 0.0054);Gain of disorder (P = 0.0054);
MVP		0.33
MPC		0.21
ClinPred		0.0093	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.56

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: rs777117857; hg19: chr10-72432613;