Genetic Variant ADAMTS7:p.His1568Gln (chr15-78763735-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014272.5(ADAMTS7):c.4704C>G(p.His1568Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,782 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADAMTS7
NM_014272.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.404

Variant links:

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]

ADAMTS7 links:

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ACMG classification

Classification made for transcript

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=0.072958976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS7	NM_014272.5 link	c.4704C>G	p.His1568Gln	missense_variant	Exon 22 of 24	ENST00000388820.5	NP_055087.2	Q9UKP4Q9UFZ4
ADAMTS7	XM_047432122.1 link	c.4704C>G	p.His1568Gln	missense_variant	Exon 22 of 24		XP_047288078.1
ADAMTS7	XM_047432123.1 link	c.3945C>G	p.His1315Gln	missense_variant	Exon 21 of 23		XP_047288079.1
ADAMTS7	XM_011521166.3 link	c.2958C>G	p.His986Gln	missense_variant	Exon 11 of 13		XP_011519468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS7	ENST00000388820.5 link	c.4704C>G	p.His1568Gln	missense_variant	Exon 22 of 24	1	NM_014272.5	ENSP00000373472.4		Q9UKP4
ADAMTS7	ENST00000569934.1 link	n.*216C>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000440

AC:

AN:

227422

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125360

show subpopulations

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:

0.0000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1440782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715254

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4704C>G (p.H1568Q) alteration is located in exon 22 (coding exon 22) of the ADAMTS7 gene. This alteration results from a C to G substitution at nucleotide position 4704, causing the histidine (H) at amino acid position 1568 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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.97

DANN

Benign

0.91

DEOGEN2

Benign

0.043

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.13

M_CAP

Benign

0.0096

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.69

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.095

Sift

Benign

0.48

Sift4G

Benign

0.45

Polyphen

0.13

Vest4

0.24

MutPred

0.30

Loss of catalytic residue at H1568 (P = 0.0447);

MVP

0.092

MPC

0.20

ClinPred

0.16

GERP RS

1.2

Varity_R

0.17

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over