5-65242190-G-A

Position:

• chr5-65242190-G-A

Variant summary

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

The NM_197941.4(ADAMTS6):​c.1847C>T​(p.Ser616Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS6 NM_197941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.45

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]

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=0.3172297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS6	NM_197941.4	c.1847C>T	p.Ser616Phe	missense_variant	15/25	ENST00000381055.8	NP_922932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS6	ENST00000381055.8	c.1847C>T	p.Ser616Phe	missense_variant	15/25	1	NM_197941.4	ENSP00000370443	P1
ADAMTS6	ENST00000470597.5	n.1726C>T		non_coding_transcript_exon_variant	13/18	1
ADAMTS6	ENST00000464680.6	n.1865C>T		non_coding_transcript_exon_variant	14/19	5
ADAMTS6	ENST00000381052.8	c.*1119C>T		3_prime_UTR_variant, NMD_transcript_variant	16/26	2		ENSP00000424377

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443372 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 717754

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 01, 2022

The c.1847C>T (p.S616F) alteration is located in exon 15 (coding exon 14) of the ADAMTS6 gene. This alteration results from a C to T substitution at nucleotide position 1847, causing the serine (S) at amino acid position 616 to be replaced by a phenylalanine (F). 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	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.41	B
Vest4		0.25
MutPred		0.38		Loss of glycosylation at S616 (P = 0.034);
MVP		0.27
MPC		0.57
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.63

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: chr5-64538017;