11-130408590-C-G

Variant names:

• chr11-130408590-C-G
• rs537374281
• NM_007037.6:c.1973G>C

Variant summary

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

The NM_007037.6(ADAMTS8):​c.1973G>C​(p.Arg658Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R658H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS8 NM_007037.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

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]

ZBTB44-DT (HGNC:54265): (ZBTB44 divergent transcript)

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_007037.6. 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
	ADAMTS8	NM_007037.6	MANE Select	c.1973G>C	p.Arg658Pro	missense	Exon 8 of 9	NP_008968.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS8	ENST00000257359.7	TSL:1 MANE Select	c.1973G>C	p.Arg658Pro	missense	Exon 8 of 9	ENSP00000257359.6	Q9UP79
	ADAMTS8	ENST00000912959.1		c.1970G>C	p.Arg657Pro	missense	Exon 8 of 9	ENSP00000583018.1
	ADAMTS8	ENST00000875535.1		c.1925G>C	p.Arg642Pro	missense	Exon 8 of 9	ENSP00000545594.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.030
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.9
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.80	P
Vest4		0.58
MutPred		0.61		Loss of catalytic residue at R658 (P = 0.0094)
MVP		0.72
MPC		0.62
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.61
gMVP		0.76
Mutation Taster		=72/28	polymorphism

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

dbSNP: rs537374281; hg19: chr11-130278485;