chr10-70741007-T-C

Position:

• chr10-70741007-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000373207.2(ADAMTS14):​c.1769T>C​(p.Leu590Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 1,613,930 control chromosomes in the GnomAD database, including 593,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.82 (51169 hom., cov: 33)
  • Exomes 𝑓: 0.86 (542159 hom.)
• Consequence: ADAMTS14 ENST00000373207.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.911

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8301546E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS14	NM_080722.4	c.1769T>C	p.Leu590Pro	missense_variant	12/22	ENST00000373207.2	NP_542453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.1769T>C	p.Leu590Pro	missense_variant	12/22	1	NM_080722.4	ENSP00000362303	P4
ADAMTS14	ENST00000373208.5	c.1778T>C	p.Leu593Pro	missense_variant	12/22	2		ENSP00000362304	A2

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124101 AN: 152080 Hom.: 51153 Cov.: 33

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.752

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.796

GnomAD3 exomes AF: 0.838 AC: 210551 AN: 251132 Hom.: 89101 AF XY: 0.846 AC XY: 114863 AN XY: 135762

Gnomad AFR exome AF: 0.703

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.880

Gnomad EAS exome AF: 0.919

Gnomad SAS exome AF: 0.856

Gnomad FIN exome AF: 0.934

Gnomad NFE exome AF: 0.861

Gnomad OTH exome AF: 0.845

GnomAD4 exome AF: 0.860 AC: 1257062 AN: 1461732 Hom.: 542159 Cov.: 68 AF XY: 0.861 AC XY: 626176 AN XY: 727166

Gnomad4 AFR exome AF: 0.705

Gnomad4 AMR exome AF: 0.703

Gnomad4 ASJ exome AF: 0.878

Gnomad4 EAS exome AF: 0.922

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.926

Gnomad4 NFE exome AF: 0.866

Gnomad4 OTH exome AF: 0.855

GnomAD4 genome AF: 0.816 AC: 124164 AN: 152198 Hom.: 51169 Cov.: 33 AF XY: 0.819 AC XY: 60946 AN XY: 74434

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.921

Gnomad4 SAS AF: 0.859

Gnomad4 FIN AF: 0.937

Gnomad4 NFE AF: 0.865

Gnomad4 OTH AF: 0.798

Alfa AF: 0.850 Hom.: 115870

Bravo AF: 0.794

TwinsUK AF: 0.859 AC: 3184

ALSPAC AF: 0.871 AC: 3356

ESP6500AA AF: 0.709 AC: 3122

ESP6500EA AF: 0.859 AC: 7391

ExAC AF: 0.840 AC: 101944

Asia WGS AF: 0.864 AC: 3000 AN: 3478

EpiCase AF: 0.853

EpiControl AF: 0.849

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.6
DANN	Benign	0.91
DEOGEN2	Benign	0.011	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.23	T;T
MetaRNN	Benign	0.0000018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	.;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.051
Sift	Benign	0.41	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0	.;B
Vest4		0.038
MPC		0.27
ClinPred		0.0014	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.32

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: rs10823607; hg19: chr10-72500763;