1-161198407-C-T

Variant names:

• chr1-161198407-C-T
• rs748250685
• NM_005099.6:c.221G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005099.6(ADAMTS4):​c.221G>A​(p.Gly74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,453,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ADAMTS4 NM_005099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• Publications: 1 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 disease

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

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10696402).

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.221G>A	p.Gly74Asp	missense	Exon 1 of 9	NP_005090.3
	ADAMTS4	NM_001320336.3		c.221G>A	p.Gly74Asp	missense	Exon 1 of 9	NP_001307265.1	O75173-2
	NDUFS2	NM_001377298.1		c.-240+920C>T		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.221G>A	p.Gly74Asp	missense	Exon 1 of 9	ENSP00000356975.4	O75173-1
	ADAMTS4	ENST00000367995.3	TSL:1	c.221G>A	p.Gly74Asp	missense	Exon 1 of 2	ENSP00000356974.3	Q5VTW1
	ADAMTS4	ENST00000926274.1		c.221G>A	p.Gly74Asp	missense	Exon 1 of 9	ENSP00000596333.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000871 AC: 2 AN: 229632 AF XY: 0.00000794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000585

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000986

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1453674 Hom.: 0 Cov.: 32 AF XY: 0.00000553 AC XY: 4 AN XY: 722808

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 43492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 85442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1108748

Other (OTH) AF: 0.0000167 AC: 1 AN: 59982

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

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	0.074
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.014
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.046
Sift	Benign	0.30	T
Sift4G	Uncertain	0.059	T
Polyphen		0.79	P
Vest4		0.16
MutPred		0.46		Gain of solvent accessibility (P = 0.1014)
MVP		0.68
MPC		0.42
ClinPred		0.11	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.44
Mutation Taster		=68/32	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: rs748250685; hg19: chr1-161168197;