NM_005099.6:c.551A>G

Variant names:

• chr1-161198077-T-C
• rs540420970
• NM_005099.6:c.551A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005099.6(ADAMTS4):​c.551A>G​(p.Lys184Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: ADAMTS4 NM_005099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021542132).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005099.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS4	NM_005099.6	MANE Select	c.551A>G	p.Lys184Arg	missense	Exon 1 of 9	NP_005090.3
	ADAMTS4	NM_001320336.3		c.551A>G	p.Lys184Arg	missense	Exon 1 of 9	NP_001307265.1	O75173-2
	NDUFS2	NM_001377298.1		c.-240+590T>C		intron	N/A	NP_001364227.1	O75306-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS4	ENST00000367996.6	TSL:1 MANE Select	c.551A>G	p.Lys184Arg	missense	Exon 1 of 9	ENSP00000356975.4	O75173-1
	ADAMTS4	ENST00000367995.3	TSL:1	c.551A>G	p.Lys184Arg	missense	Exon 1 of 2	ENSP00000356974.3	Q5VTW1
	ADAMTS4	ENST00000926274.1		c.551A>G	p.Lys184Arg	missense	Exon 1 of 9	ENSP00000596333.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000564 AC: 14 AN: 248106 AF XY: 0.0000596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459910 Hom.: 1 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 725916

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000453 AC: 39 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110606

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.077
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.35		Gain of catalytic residue at S185 (P = 0.0062)
MVP		0.57
MPC		0.89
ClinPred		0.087	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.49
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs540420970; hg19: chr1-161167867;