10-70741007-T-C

Variant names:

• chr10-70741007-T-C
• rs10823607
• NM_080722.4:c.1769T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080722.4(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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L590R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.82 (51169 hom., cov: 33)
  • Exomes 𝑓: 0.86 (542159 hom.)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.911
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080722.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS14	NM_080722.4	MANE Select	c.1769T>C	p.Leu590Pro	missense	Exon 12 of 22	NP_542453.2	Q8WXS8-1
	ADAMTS14	NM_139155.3		c.1778T>C	p.Leu593Pro	missense	Exon 12 of 22	NP_631894.2	Q8WXS8-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS14	ENST00000373207.2	TSL:1 MANE Select	c.1769T>C	p.Leu590Pro	missense	Exon 12 of 22	ENSP00000362303.1	Q8WXS8-1
	ADAMTS14	ENST00000886732.1		c.1778T>C	p.Leu593Pro	missense	Exon 12 of 22	ENSP00000556791.1
	ADAMTS14	ENST00000373208.5	TSL:2	c.1778T>C	p.Leu593Pro	missense	Exon 12 of 22	ENSP00000362304.1	Q8WXS8-4

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

GnomAD2 exomes AF: 0.838 AC: 210551 AN: 251132 AF XY: 0.846

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 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

African (AFR) AF: 0.705 AC: 23590 AN: 33476

American (AMR) AF: 0.703 AC: 31451 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 22953 AN: 26134

East Asian (EAS) AF: 0.922 AC: 36583 AN: 39698

South Asian (SAS) AF: 0.858 AC: 73981 AN: 86256

European-Finnish (FIN) AF: 0.926 AC: 49389 AN: 53348

Middle Eastern (MID) AF: 0.831 AC: 4791 AN: 5768

European-Non Finnish (NFE) AF: 0.866 AC: 962700 AN: 1111940

Other (OTH) AF: 0.855 AC: 51624 AN: 60392

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

African (AFR) AF: 0.709 AC: 29396 AN: 41480

American (AMR) AF: 0.751 AC: 11480 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3049 AN: 3472

East Asian (EAS) AF: 0.921 AC: 4768 AN: 5176

South Asian (SAS) AF: 0.859 AC: 4146 AN: 4826

European-Finnish (FIN) AF: 0.937 AC: 9959 AN: 10624

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58824 AN: 68010

Other (OTH) AF: 0.798 AC: 1687 AN: 2114

Alfa AF: 0.841 Hom.: 151254

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 v4.9

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
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.91
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.051
Sift	Benign	0.41	T
Sift4G	Benign	0.24	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10823607; hg19: chr10-72500763; COSMIC: COSV107473810;