1-161198214-C-T

Variant names:

• chr1-161198214-C-T
• rs33941127
• NM_005099.6:c.414G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.82
• Publications: 21 publications found

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]

NDUFS2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 6

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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	c.414G>A	p.Ser138Ser	synonymous_variant	Exon 1 of 9	ENST00000367996.6	NP_005090.3

Ensembl

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

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

GnomAD2 exomes AF: 0.284 AC: 70721 AN: 249388 AF XY: 0.280

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 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

African (AFR) AF: 0.381 AC: 12770 AN: 33480

American (AMR) AF: 0.354 AC: 15819 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6206 AN: 26134

East Asian (EAS) AF: 0.494 AC: 19610 AN: 39700

South Asian (SAS) AF: 0.355 AC: 30603 AN: 86258

European-Finnish (FIN) AF: 0.227 AC: 12129 AN: 53386

Middle Eastern (MID) AF: 0.271 AC: 1563 AN: 5768

European-Non Finnish (NFE) AF: 0.209 AC: 232176 AN: 1111996

Other (OTH) AF: 0.255 AC: 15421 AN: 60392

GnomAD4 genome AF: 0.276 AC: 41972 AN: 152016 Hom.: 6342 Cov.: 32 AF XY: 0.280 AC XY: 20829 AN XY: 74320

African (AFR) AF: 0.367 AC: 15201 AN: 41468

American (AMR) AF: 0.283 AC: 4325 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 846 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2477 AN: 5140

South Asian (SAS) AF: 0.385 AC: 1853 AN: 4818

European-Finnish (FIN) AF: 0.233 AC: 2470 AN: 10598

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13956 AN: 67932

Other (OTH) AF: 0.286 AC: 602 AN: 2106

Alfa AF: 0.225 Hom.: 4962

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
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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