15-78764056-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014272.5(ADAMTS7):c.4463A>G(p.Gln1488Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000577 in 1,385,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: ADAMTS7 NM_014272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35358998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS7	NM_014272.5	c.4463A>G	p.Gln1488Arg	missense_variant	21/24	ENST00000388820.5
ADAMTS7	XM_047432122.1	c.4463A>G	p.Gln1488Arg	missense_variant	21/24
ADAMTS7	XM_047432123.1	c.3704A>G	p.Gln1235Arg	missense_variant	20/23
ADAMTS7	XM_011521166.3	c.2717A>G	p.Gln906Arg	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS7	ENST00000388820.5	c.4463A>G	p.Gln1488Arg	missense_variant	21/24	1	NM_014272.5	P1
ADAMTS7	ENST00000569934.1	n.603A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000683 AC: 1 AN: 146430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 77842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000577 AC: 8 AN: 1385580 Hom.: 0 Cov.: 31 AF XY: 0.00000587 AC XY: 4 AN XY: 681850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000653

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 34

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 09, 2022

The c.4463A>G (p.Q1488R) alteration is located in exon 21 (coding exon 21) of the ADAMTS7 gene. This alteration results from a A to G substitution at nucleotide position 4463, causing the glutamine (Q) at amino acid position 1488 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.91	L
MutationTaster	Benign	0.86	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.069
Sift	Benign	0.34	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.34
MutPred		0.28		Gain of MoRF binding (P = 0.0249);
MVP		0.54
MPC		0.70
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.33

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: rs749040886; hg19: chr15-79056398;