5-65151950-C-T

Variant names:

• chr5-65151950-C-T
• rs17206779
• NM_197941.4:c.3245-5G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_197941.4(ADAMTS6):​c.3245-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,607,320 control chromosomes in the GnomAD database, including 204,239 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (15123 hom., cov: 32)
  • Exomes 𝑓: 0.51 (189116 hom.)
• Consequence: ADAMTS6 NM_197941.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.622
• Publications: 24 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

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.3245-5G>A		splice_region intron	N/A	NP_922932.2	Q9UKP5-1
	ADAMTS6	NR_135689.2		n.4253-5G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS6	ENST00000381055.8	TSL:1 MANE Select	c.3245-5G>A		splice_region intron	N/A	ENSP00000370443.3	Q9UKP5-1
	ADAMTS6	ENST00000314351.9	TSL:2	n.905-5G>A		splice_region intron	N/A
	ADAMTS6	ENST00000381052.8	TSL:2	n.*2517-5G>A		splice_region intron	N/A	ENSP00000424377.1	Q9UKP5-4

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64565 AN: 151842 Hom.: 15122 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.480 AC: 120349 AN: 250700 AF XY: 0.483

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.357

Gnomad FIN exome AF: 0.527

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.505 AC: 735335 AN: 1455356 Hom.: 189116 Cov.: 31 AF XY: 0.504 AC XY: 364488 AN XY: 723516

African (AFR) AF: 0.211 AC: 7030 AN: 33374

American (AMR) AF: 0.538 AC: 24039 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12562 AN: 26046

East Asian (EAS) AF: 0.362 AC: 14320 AN: 39586

South Asian (SAS) AF: 0.427 AC: 36654 AN: 85852

European-Finnish (FIN) AF: 0.537 AC: 28575 AN: 53206

Middle Eastern (MID) AF: 0.436 AC: 2499 AN: 5732

European-Non Finnish (NFE) AF: 0.524 AC: 580322 AN: 1106758

Other (OTH) AF: 0.488 AC: 29334 AN: 60128

GnomAD4 genome AF: 0.425 AC: 64567 AN: 151964 Hom.: 15123 Cov.: 32 AF XY: 0.423 AC XY: 31435 AN XY: 74248

African (AFR) AF: 0.219 AC: 9058 AN: 41446

American (AMR) AF: 0.496 AC: 7573 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1645 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1798 AN: 5148

South Asian (SAS) AF: 0.418 AC: 2011 AN: 4810

European-Finnish (FIN) AF: 0.505 AC: 5331 AN: 10546

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35611 AN: 67954

Other (OTH) AF: 0.454 AC: 958 AN: 2112

Alfa AF: 0.489 Hom.: 89909

Bravo AF: 0.418

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.84
PhyloP100		-0.62
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

dbSNP: rs17206779; hg19: chr5-64447777; COSMIC: COSV58683352;