Genetic Variant ADAMTS4:p.Ser138Ser (chr1-161198214-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_005099.6(ADAMTS4):c.414G>A(p.Ser138Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,613,846 control chromosomes in the GnomAD database, including 50,600 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6342 hom., cov: 32)

Exomes 𝑓: 0.24 ( 44258 hom. )

Consequence

ADAMTS4
NM_005099.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.82

Variant links:

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]

ADAMTS4 links:

NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

NDUFS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP7

Synonymous conserved (PhyloP=-3.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS4	NM_005099.6 link	c.414G>A	p.Ser138Ser	synonymous_variant	Exon 1 of 9	ENST00000367996.6	NP_005090.3	O75173-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS4	ENST00000367996.6 link	c.414G>A	p.Ser138Ser	synonymous_variant	Exon 1 of 9	1	NM_005099.6	ENSP00000356975.4		O75173-1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41903

AN:

151898

Hom.:

6323

Cov.:

show subpopulations

Gnomad AFR

AF:

0.366

Gnomad AMI

AF:

0.176

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.281

GnomAD3 exomes

AF:

0.284

AC:

70721

AN:

249388

Hom.:

11124

AF XY:

0.280

AC XY:

37754

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.377

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.237

Gnomad EAS exome

AF:

0.491

Gnomad SAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.207

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.237

AC:

346297

AN:

1461830

Hom.:

44258

Cov.:

AF XY:

0.239

AC XY:

173816

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.381

Gnomad4 AMR exome

AF:

0.354

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.494

Gnomad4 SAS exome

AF:

0.355

Gnomad4 FIN exome

AF:

0.227

Gnomad4 NFE exome

AF:

0.209

Gnomad4 OTH exome

AF:

0.255

GnomAD4 genome

AF:

0.276

AC:

41972

AN:

152016

Hom.:

6342

Cov.:

AF XY:

0.280

AC XY:

20829

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.367

Gnomad4 AMR

AF:

0.283

Gnomad4 ASJ

AF:

0.244

Gnomad4 EAS

AF:

0.482

Gnomad4 SAS

AF:

0.385

Gnomad4 FIN

AF:

0.233

Gnomad4 NFE

AF:

0.205

Gnomad4 OTH

AF:

0.286

Alfa

AF:

0.214

Hom.:

2819

Bravo

AF:

0.288

Asia WGS

AF:

0.428

AC:

1487

AN:

3478

EpiCase

AF:

0.206

EpiControl

AF:

0.209

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.4

DANN

Benign

0.89

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over