NM_197941.4:c.2627T>C

Variant names:

• chr5-65197100-A-G
• NM_197941.4:c.2627T>C

Variant summary

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

The NM_197941.4(ADAMTS6):​c.2627T>C​(p.Val876Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS6 NM_197941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_197941.4. 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
	ADAMTS6	NM_197941.4	MANE Select	c.2627T>C	p.Val876Ala	missense	Exon 21 of 25	NP_922932.2	Q9UKP5-1
	ADAMTS6	NR_135689.2		n.3635T>C		non_coding_transcript_exon	Exon 22 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS6	ENST00000381055.8	TSL:1 MANE Select	c.2627T>C	p.Val876Ala	missense	Exon 21 of 25	ENSP00000370443.3	Q9UKP5-1
	ADAMTS6	ENST00000314351.9	TSL:2	n.287T>C		non_coding_transcript_exon	Exon 2 of 6
	ADAMTS6	ENST00000381052.8	TSL:2	n.*1899T>C		non_coding_transcript_exon	Exon 22 of 26	ENSP00000424377.1	Q9UKP5-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.052	T
Polyphen		0.58	P
Vest4		0.85
MutPred		0.39		Gain of disorder (P = 0.1037)
MVP		0.20
MPC		0.61
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.40
gMVP		0.66
Mutation Taster		=45/55	disease causing

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

hg19: chr5-64492927;