15-78763754-G-A

Variant summary

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

The NM_014272.5(ADAMTS7):c.4685C>T(p.Thr1562Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,598,476 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ADAMTS7 NM_014272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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=0.088183016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS7	NM_014272.5	c.4685C>T	p.Thr1562Ile	missense_variant	22/24	ENST00000388820.5
ADAMTS7	XM_047432122.1	c.4685C>T	p.Thr1562Ile	missense_variant	22/24
ADAMTS7	XM_047432123.1	c.3926C>T	p.Thr1309Ile	missense_variant	21/23
ADAMTS7	XM_011521166.3	c.2939C>T	p.Thr980Ile	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS7	ENST00000388820.5	c.4685C>T	p.Thr1562Ile	missense_variant	22/24	1	NM_014272.5	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000877 AC: 20 AN: 228044 Hom.: 0 AF XY: 0.0000798 AC XY: 10 AN XY: 125378

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.0000600

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: 0.00000976

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000346 AC: 50 AN: 1446110 Hom.: 0 Cov.: 31 AF XY: 0.0000306 AC XY: 22 AN XY: 718366

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.0000454

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.000354 AC: 54 AN: 152366 Hom.: 0 Cov.: 34 AF XY: 0.000242 AC XY: 18 AN XY: 74510

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.00140 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

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

Jul 06, 2021

The c.4685C>T (p.T1562I) alteration is located in exon 22 (coding exon 22) of the ADAMTS7 gene. This alteration results from a C to T substitution at nucleotide position 4685, causing the threonine (T) at amino acid position 1562 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	0.19
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	0.062
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	0.54	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.31
MVP		0.54
MPC		0.69
ClinPred		0.14	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.15

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: rs368609643; hg19: chr15-79056096;