15-78762415-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.4891G>A(p.Val1631Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,488,788 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 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ADAMTS7 NM_014272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.124

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=0.013550401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS7	NM_014272.5	c.4891G>A	p.Val1631Ile	missense_variant	23/24	ENST00000388820.5
ADAMTS7	XM_047432122.1	c.4891G>A	p.Val1631Ile	missense_variant	23/24
ADAMTS7	XM_047432123.1	c.4132G>A	p.Val1378Ile	missense_variant	22/23
ADAMTS7	XM_011521166.3	c.3145G>A	p.Val1049Ile	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS7	ENST00000388820.5	c.4891G>A	p.Val1631Ile	missense_variant	23/24	1	NM_014272.5	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0000291 AC: 4 AN: 137612 Hom.: 0 AF XY: 0.0000135 AC XY: 1 AN XY: 73854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000532

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000942

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000160

Gnomad OTH exome AF: 0.000324

GnomAD4 exome AF: 0.0000202 AC: 27 AN: 1336442 Hom.: 0 Cov.: 30 AF XY: 0.0000198 AC XY: 13 AN XY: 657182

Gnomad4 AFR exome AF: 0.0000350

Gnomad4 AMR exome AF: 0.000204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000593

Gnomad4 SAS exome AF: 0.0000146

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000763

Gnomad4 OTH exome AF: 0.000165

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74494

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.000540

ExAC AF: 0.00000831 AC: 1

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

Jan 08, 2024

The c.4891G>A (p.V1631I) alteration is located in exon 23 (coding exon 23) of the ADAMTS7 gene. This alteration results from a G to A substitution at nucleotide position 4891, causing the valine (V) at amino acid position 1631 to be replaced by an isoleucine (I). 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	0.072
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.51
Dann	Benign	0.78
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.029
Sift	Benign	0.52	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.065
MutPred		0.21		Loss of glycosylation at P1633 (P = 0.5633);
MVP		0.16
MPC		0.13
ClinPred		0.014	T
GERP RS		-8.2
Varity_R		0.018
gMVP		0.10

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: rs150570920; hg19: chr15-79054757; COSMIC: COSV105321629; COSMIC: COSV105321629;