chr1-161193247-T-C

Position:

• chr1-161193247-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005099.6(ADAMTS4):​c.1877A>G​(p.Gln626Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,613,388 control chromosomes in the GnomAD database, including 320,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.62 (30005 hom., cov: 32)
  • Exomes 𝑓: 0.63 (290652 hom.)
• Consequence: ADAMTS4 NM_005099.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.153451E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS4	NM_005099.6	c.1877A>G	p.Gln626Arg	missense_variant	7/9	ENST00000367996.6	NP_005090.3
ADAMTS4	NM_001320336.3	c.1877A>G	p.Gln626Arg	missense_variant	7/9		NP_001307265.1
ADAMTS4	XM_047434904.1	c.1735+393A>G		intron_variant			XP_047290860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS4	ENST00000367996.6	c.1877A>G	p.Gln626Arg	missense_variant	7/9	1	NM_005099.6	ENSP00000356975.4

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94879 AN: 151908 Hom.: 29962 Cov.: 32

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.631

GnomAD3 exomes AF: 0.665 AC: 166295 AN: 249938 Hom.: 56580 AF XY: 0.664 AC XY: 89738 AN XY: 135218

Gnomad AFR exome AF: 0.611

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.895

Gnomad SAS exome AF: 0.747

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.627 AC: 915809 AN: 1461362 Hom.: 290652 Cov.: 65 AF XY: 0.628 AC XY: 456613 AN XY: 726954

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.767

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.920

Gnomad4 SAS exome AF: 0.741

Gnomad4 FIN exome AF: 0.601

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.625 AC: 94974 AN: 152026 Hom.: 30005 Cov.: 32 AF XY: 0.630 AC XY: 46806 AN XY: 74306

Gnomad4 AFR AF: 0.605

Gnomad4 AMR AF: 0.690

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.889

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.616

Gnomad4 NFE AF: 0.595

Gnomad4 OTH AF: 0.636

Alfa AF: 0.610 Hom.: 65026

Bravo AF: 0.635

TwinsUK AF: 0.607 AC: 2249

ALSPAC AF: 0.598 AC: 2305

ESP6500AA AF: 0.608 AC: 2678

ESP6500EA AF: 0.600 AC: 5162

ExAC AF: 0.660 AC: 80160

Asia WGS AF: 0.821 AC: 2850 AN: 3478

EpiCase AF: 0.598

EpiControl AF: 0.595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.2
DANN	Benign	0.70
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.020	T
MetaRNN	Benign	6.2e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.31
ClinPred		0.00066	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.36

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: rs4233367; hg19: chr1-161163037; COSMIC: COSV63490278; COSMIC: COSV63490278;