11-130408833-G-A

Variant names:

• chr11-130408833-G-A
• rs34821407
• NM_007037.6:c.1858C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007037.6(ADAMTS8):​c.1858C>T​(p.Arg620Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ADAMTS8 NM_007037.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.958

Genes affected

ADAMTS8 (HGNC:224): (ADAM metallopeptidase with thrombospondin type 1 motif 8) 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. This enzyme contains two C-terminal TS motifs, and disrupts angiogenesis in vivo. A number of disorders have been mapped in the vicinity of this gene, most notably lung neoplasms. Reduced expression of this gene has been observed in multiple human cancers and this gene has been proposed as a potential tumor suppressor. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS8	NM_007037.6	c.1858C>T	p.Arg620Trp	missense_variant	Exon 7 of 9	ENST00000257359.7	NP_008968.4
ADAMTS8	XM_017017145.2	c.1810C>T	p.Arg604Trp	missense_variant	Exon 7 of 9		XP_016872634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS8	ENST00000257359.7	c.1858C>T	p.Arg620Trp	missense_variant	Exon 7 of 9	1	NM_007037.6	ENSP00000257359.6
ADAMTS8	ENST00000531752.1	n.805C>T		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248750 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134902

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461282 Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 105 AN XY: 726882

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74442

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000461

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1858C>T (p.R620W) alteration is located in exon 7 (coding exon 7) of the ADAMTS8 gene. This alteration results from a C to T substitution at nucleotide position 1858, causing the arginine (R) at amino acid position 620 to be replaced by a tryptophan (W). 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	0.17
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.084	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.94
MPC		0.89
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.51
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs34821407; hg19: chr11-130278728; COSMIC: COSV57291705;