12-43376551-C-T

Variant names:

• chr12-43376551-C-T
• rs768036937
• NM_025003.5:c.5098G>A

Variant summary

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

The NM_025003.5(ADAMTS20):​c.5098G>A​(p.Ala1700Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 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. A1700S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS20 NM_025003.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397

Genes affected

ADAMTS20 (HGNC:17178): (ADAM metallopeptidase with thrombospondin type 1 motif 20) The protein encoded by this gene is a member of the ADAMTS family of zinc-dependent proteases. The encoded protein has a signal peptide that is cleaved to release the mature peptide, which is secreted and found in the extracellular matrix. This protein may be involved in tissue remodeling. [provided by RefSeq, Sep 2011]

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
ADAMTS20	NM_025003.5	c.5098G>A	p.Ala1700Thr	missense_variant	Exon 33 of 39	ENST00000389420.8	NP_079279.3
ADAMTS20	XM_011538754.3	c.5101G>A	p.Ala1701Thr	missense_variant	Exon 33 of 39		XP_011537056.1
ADAMTS20	XM_017019979.2	c.3886G>A	p.Ala1296Thr	missense_variant	Exon 26 of 32		XP_016875468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS20	ENST00000389420.8	c.5098G>A	p.Ala1700Thr	missense_variant	Exon 33 of 39	1	NM_025003.5	ENSP00000374071.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250100 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.73
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.015
Sift	Benign	0.66	T
Sift4G	Benign	0.60	T
Vest4		0.25
MutPred		0.32		Gain of catalytic residue at G1699 (P = 0.0107);
MVP		0.66
MPC		0.039
ClinPred		0.13	T
GERP RS		2.9
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 3
DS_DL_spliceai		0.26		Position offset: -27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768036937; hg19: chr12-43770354;