1-161198401-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005099.6(ADAMTS4):c.227G>A(p.Gly76Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000092 in 1,608,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ADAMTS4 NM_005099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004328966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS4	NM_005099.6	c.227G>A	p.Gly76Asp	missense_variant	1/9	ENST00000367996.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS4	ENST00000367996.6	c.227G>A	p.Gly76Asp	missense_variant	1/9	1	NM_005099.6	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000145 AC: 34 AN: 233890 Hom.: 0 AF XY: 0.0000623 AC XY: 8 AN XY: 128316

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 60 AN: 1456306 Hom.: 0 Cov.: 32 AF XY: 0.0000387 AC XY: 28 AN XY: 724320

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.0000910

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74478

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00207 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000199 AC: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.227G>A (p.G76D) alteration is located in exon 1 (coding exon 1) of the ADAMTS4 gene. This alteration results from a G to A substitution at nucleotide position 227, causing the glycine (G) at amino acid position 76 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.048
Sift	Benign	0.39	T;T
Sift4G	Benign	0.15	T;D
Polyphen		0.0010	B;B
Vest4		0.17
MVP		0.44
MPC		0.38
ClinPred		0.0097	T
GERP RS		3.6
Varity_R		0.092
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs148118422; hg19: chr1-161168191;