15-78763779-C-T

Variant summary

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

The NM_014272.5(ADAMTS7):c.4660G>A(p.Glu1554Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000313 in 1,594,968 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ADAMTS7 NM_014272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

ADAMTS7 (HGNC:223): (ADAM metallopeptidase with thrombospondin type 1 motif 7) The protein encoded by this gene is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. Members of this 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 contains two C-terminal TS motifs and may regulate vascular smooth muscle cell (VSMC) migration. Mutations in this gene may be associated with susceptibility to coronary artery disease. [provided by RefSeq, Feb 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=0.23341921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS7	NM_014272.5	c.4660G>A	p.Glu1554Lys	missense_variant	22/24	ENST00000388820.5
ADAMTS7	XM_047432122.1	c.4660G>A	p.Glu1554Lys	missense_variant	22/24
ADAMTS7	XM_047432123.1	c.3901G>A	p.Glu1301Lys	missense_variant	21/23
ADAMTS7	XM_011521166.3	c.2914G>A	p.Glu972Lys	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS7	ENST00000388820.5	c.4660G>A	p.Glu1554Lys	missense_variant	22/24	1	NM_014272.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152232 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000370 AC: 8 AN: 216248 Hom.: 0 AF XY: 0.0000169 AC XY: 2 AN XY: 118358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000120

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000291 AC: 42 AN: 1442736 Hom.: 0 Cov.: 31 AF XY: 0.0000223 AC XY: 16 AN XY: 716598

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.0000593

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000280

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152232 Hom.: 1 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000500 AC: 6

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

Jun 22, 2021

The c.4660G>A (p.E1554K) alteration is located in exon 22 (coding exon 22) of the ADAMTS7 gene. This alteration results from a G to A substitution at nucleotide position 4660, causing the glutamic acid (E) at amino acid position 1554 to be replaced by a lysine (K). 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	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.49	N
MutationTaster	Benign	0.53	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.042
Sift	Benign	0.047	D
Sift4G	Uncertain	0.039	D
Polyphen		0.64	P
Vest4		0.49
MutPred		0.37		Gain of methylation at E1554 (P = 0.0028);
MVP		0.57
MPC		0.66
ClinPred		0.16	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.26

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: rs776529306; hg19: chr15-79056121;