15-78764041-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014272.5(ADAMTS7):c.4478G>A(p.Arg1493Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000448 in 1,539,246 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: ADAMTS7 NM_014272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023416042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS7	NM_014272.5	c.4478G>A	p.Arg1493Gln	missense_variant	21/24	ENST00000388820.5
ADAMTS7	XM_047432122.1	c.4478G>A	p.Arg1493Gln	missense_variant	21/24
ADAMTS7	XM_047432123.1	c.3719G>A	p.Arg1240Gln	missense_variant	20/23
ADAMTS7	XM_011521166.3	c.2732G>A	p.Arg911Gln	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS7	ENST00000388820.5	c.4478G>A	p.Arg1493Gln	missense_variant	21/24	1	NM_014272.5	P1
ADAMTS7	ENST00000569934.1	n.618G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152262 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000820 AC: 12 AN: 146276 Hom.: 0 AF XY: 0.000116 AC XY: 9 AN XY: 77706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000470

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000461 AC: 64 AN: 1386984 Hom.: 0 Cov.: 31 AF XY: 0.0000644 AC XY: 44 AN XY: 682942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000580

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000526

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000177

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152262 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74394

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000748 AC: 8

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

Sep 22, 2023

The c.4478G>A (p.R1493Q) alteration is located in exon 21 (coding exon 21) of the ADAMTS7 gene. This alteration results from a G to A substitution at nucleotide position 4478, causing the arginine (R) at amino acid position 1493 to be replaced by a glutamine (Q). 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	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	0.55	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.035
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.26	B
Vest4		0.11
MutPred		0.23		Loss of phosphorylation at T1492 (P = 0.1073);
MVP		0.23
MPC		0.21
ClinPred		0.050	T
GERP RS		1.1
Varity_R		0.034
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs750358699; hg19: chr15-79056383; COSMIC: COSV101183290; COSMIC: COSV101183290;