1-161198214-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005099.6(ADAMTS4):c.414G>A(p.Ser138=) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.82

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]

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]

ACMG classification

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/exons	MANE	UniProt
ADAMTS4	NM_005099.6	c.414G>A	p.Ser138=	synonymous_variant	1/9	ENST00000367996.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS4	ENST00000367996.6	c.414G>A	p.Ser138=	synonymous_variant	1/9	1	NM_005099.6	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41903 AN: 151898 Hom.: 6323 Cov.: 32

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

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.: 38 AF XY: 0.239 AC XY: 173816 AN XY: 727218

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.: 32 AF XY: 0.280 AC XY: 20829 AN XY: 74320

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

Other links and lift over

dbSNP: rs33941127; hg19: chr1-161168004; COSMIC: COSV63487483; COSMIC: COSV63487483;