rs61573157

Positions:

• chr10-70760503-C-T

Variant summary

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

The NM_080722.4(ADAMTS14):​c.3322C>T​(p.Pro1108Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0932 in 1,613,844 control chromosomes in the GnomAD database, including 7,622 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.076 (572 hom., cov: 33)
  • Exomes 𝑓: 0.095 (7050 hom.)
• Consequence: ADAMTS14 NM_080722.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920

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=0.0017440319).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS14	NM_080722.4	c.3322C>T	p.Pro1108Ser	missense_variant	22/22	ENST00000373207.2	NP_542453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS14	ENST00000373207.2	c.3322C>T	p.Pro1108Ser	missense_variant	22/22	1	NM_080722.4	ENSP00000362303	P4
ADAMTS14	ENST00000373208.5	c.3331C>T	p.Pro1111Ser	missense_variant	22/22	2		ENSP00000362304	A2

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11539 AN: 152130 Hom.: 571 Cov.: 33

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0801

GnomAD3 exomes AF: 0.0857 AC: 21298 AN: 248402 Hom.: 1070 AF XY: 0.0883 AC XY: 11869 AN XY: 134484

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.0412

Gnomad ASJ exome AF: 0.0825

Gnomad EAS exome AF: 0.0941

Gnomad SAS exome AF: 0.0764

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0931

GnomAD4 exome AF: 0.0951 AC: 138940 AN: 1461596 Hom.: 7050 Cov.: 32 AF XY: 0.0949 AC XY: 69015 AN XY: 727072

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.0806

Gnomad4 EAS exome AF: 0.0798

Gnomad4 SAS exome AF: 0.0776

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.0890

GnomAD4 genome AF: 0.0757 AC: 11523 AN: 152248 Hom.: 572 Cov.: 33 AF XY: 0.0761 AC XY: 5663 AN XY: 74432

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.0542

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.0974

Gnomad4 SAS AF: 0.0731

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.0792

Alfa AF: 0.0884 Hom.: 279

Bravo AF: 0.0694

TwinsUK AF: 0.0998 AC: 370

ALSPAC AF: 0.104 AC: 399

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.105 AC: 906

ExAC AF: 0.0871 AC: 10577

Asia WGS AF: 0.0720 AC: 251 AN: 3478

EpiCase AF: 0.0990

EpiControl AF: 0.0982

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.36
DANN	Benign	0.24
DEOGEN2	Benign	0.011	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	.;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.013
Sift	Benign	0.87	T;T
Sift4G	Benign	0.87	T;T
Polyphen		0.0020	.;B
Vest4		0.022
MPC		0.17
ClinPred		0.00042	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61573157; hg19: chr10-72520259; COSMIC: COSV64602584;