5-65172942-T-C

Position:

• chr5-65172942-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_197941.4(ADAMTS6):​c.2977A>G​(p.Lys993Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADAMTS6 NM_197941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

ADAMTS6 (HGNC:222): (ADAM metallopeptidase with thrombospondin type 1 motif 6) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the 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 encoded preproprotein is proteolytically processed to generate the mature enzyme. Expression of this gene may be regulated by the cytokine TNF-alpha. [provided by RefSeq, Mar 2016]

ADAMTS6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADAMTS6. . Gene score misZ 3.088 (greater than the threshold 3.09). Trascript score misZ 4.203 (greater than threshold 3.09). GenCC has associacion of gene with Tourette syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2881338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS6	NM_197941.4	c.2977A>G	p.Lys993Glu	missense_variant	23/25	ENST00000381055.8	NP_922932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS6	ENST00000381055.8	c.2977A>G	p.Lys993Glu	missense_variant	23/25	1	NM_197941.4	ENSP00000370443.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

May 31, 2023

The c.2977A>G (p.K993E) alteration is located in exon 23 (coding exon 22) of the ADAMTS6 gene. This alteration results from a A to G substitution at nucleotide position 2977, causing the lysine (K) at amino acid position 993 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.040	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.20
Sift	Benign	0.89	T
Sift4G	Benign	0.96	T
Polyphen		0.0020	B
Vest4		0.70
MutPred		0.30		Loss of ubiquitination at K993 (P = 0.0034);
MVP		0.34
MPC		0.69
ClinPred		0.71	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-64468769;