5-65188201-A-G

Variant names:

• chr5-65188201-A-G
• NM_197941.4:c.2725T>C
• ADAMTS6 p.Leu909Leu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_197941.4(ADAMTS6):​c.2725T>C​(p.Leu909Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ADAMTS6 NM_197941.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP7: Synonymous conserved (PhyloP=3.24 with no splicing effect.

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.2725T>C	p.Leu909Leu	synonymous	Exon 22 of 25	NP_922932.2	Q9UKP5-1
	ADAMTS6	NR_135689.2		n.3733T>C		non_coding_transcript_exon	Exon 23 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS6	ENST00000381055.8	TSL:1 MANE Select	c.2725T>C	p.Leu909Leu	synonymous	Exon 22 of 25	ENSP00000370443.3	Q9UKP5-1
	ADAMTS6	ENST00000314351.9	TSL:2	n.385T>C		non_coding_transcript_exon	Exon 3 of 6
	ADAMTS6	ENST00000381052.8	TSL:2	n.*1997T>C		non_coding_transcript_exon	Exon 23 of 26	ENSP00000424377.1	Q9UKP5-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	5.1
DANN	Benign	0.77
PhyloP100		3.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-64484028;