1-161191380-T-C

Variant summary

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

The NM_005099.6(ADAMTS4):c.2272A>G(p.Ser758Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: ADAMTS4 NM_005099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569

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 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=0.07718742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS4	NM_005099.6	c.2272A>G	p.Ser758Gly	missense_variant	9/9	ENST00000367996.6
ADAMTS4	NM_001320336.3	c.2111A>G	p.Gln704Arg	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS4	ENST00000367996.6	c.2272A>G	p.Ser758Gly	missense_variant	9/9	1	NM_005099.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 251010 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.0000969

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

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: 0.0000621

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74378

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000273

EpiControl AF: 0.000119

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

Dec 09, 2023

The c.2272A>G (p.S758G) alteration is located in exon 9 (coding exon 9) of the ADAMTS4 gene. This alteration results from a A to G substitution at nucleotide position 2272, causing the serine (S) at amino acid position 758 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	0.076
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.68	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.068
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.29	T
Polyphen		0.011	B
Vest4		0.23
MVP		0.65
MPC		0.30
ClinPred		0.16	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.65

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: rs145548254; hg19: chr1-161161170;