1-161191151-G-C

Variant summary

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

The NM_005099.6(ADAMTS4):c.2501C>G(p.Ala834Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,555,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ADAMTS4 NM_005099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.158

Genes affected

ADAMTS4 (HGNC:220): (ADAM metallopeptidase with thrombospondin type 1 motif 4) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein 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 enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [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=0.03109911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS4	NM_005099.6	c.2501C>G	p.Ala834Gly	missense_variant	9/9	ENST00000367996.6
ADAMTS4	NM_001320336.3	c.2340C>G	p.Gly780=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS4	ENST00000367996.6	c.2501C>G	p.Ala834Gly	missense_variant	9/9	1	NM_005099.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152278 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000987 AC: 21 AN: 212744 Hom.: 0 AF XY: 0.0000699 AC XY: 8 AN XY: 114402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000296

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: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 146 AN: 1403282 Hom.: 0 Cov.: 31 AF XY: 0.0000899 AC XY: 62 AN XY: 689726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000398

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.0000984 AC: 15 AN: 152396 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74522

Gnomad4 AFR AF: 0.0000240

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: 0.000176

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000453

ExAC AF: 0.0000496 AC: 6

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

Aug 28, 2023

The c.2501C>G (p.A834G) alteration is located in exon 9 (coding exon 9) of the ADAMTS4 gene. This alteration results from a C to G substitution at nucleotide position 2501, causing the alanine (A) at amino acid position 834 to be replaced by a glycine (G). 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	0.071
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.028
Sift	Uncertain	0.014	D
Sift4G	Benign	0.27	T
Polyphen		0.057	B
Vest4		0.092
MVP		0.46
MPC		0.29
ClinPred		0.029	T
GERP RS		0.14
Varity_R		0.045
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs114600134; hg19: chr1-161160941; COSMIC: COSV63491343; COSMIC: COSV63491343;