12-43425515-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025003.5(ADAMTS20):c.4283C>T(p.Ser1428Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000528 in 1,505,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: ADAMTS20 NM_025003.5 missense, splice_region
• Scores: Splicing: ADA: 0.3101
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15621617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS20	NM_025003.5	c.4283C>T	p.Ser1428Leu	missense_variant, splice_region_variant	28/39	ENST00000389420.8
ADAMTS20	XM_011538754.3	c.4286C>T	p.Ser1429Leu	missense_variant, splice_region_variant	28/39
ADAMTS20	XM_017019979.2	c.3071C>T	p.Ser1024Leu	missense_variant, splice_region_variant	21/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS20	ENST00000389420.8	c.4283C>T	p.Ser1428Leu	missense_variant, splice_region_variant	28/39	1	NM_025003.5	P1
ADAMTS20	ENST00000553158.5	c.4283C>T	p.Ser1428Leu	missense_variant, splice_region_variant	28/29	5
ADAMTS20	ENST00000549670.5	c.1673C>T	p.Ser558Leu	missense_variant, splice_region_variant	10/11	2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000291 AC: 61 AN: 209472 Hom.: 0 AF XY: 0.000237 AC XY: 27 AN XY: 113708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.000207

GnomAD4 exome AF: 0.000549 AC: 743 AN: 1353482 Hom.: 1 Cov.: 31 AF XY: 0.000512 AC XY: 341 AN XY: 666222

Gnomad4 AFR exome AF: 0.0000992

Gnomad4 AMR exome AF: 0.0000545

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000143

Gnomad4 FIN exome AF: 0.000139

Gnomad4 NFE exome AF: 0.000679

Gnomad4 OTH exome AF: 0.000345

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74442

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000382 Hom.: 2

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.4283C>T (p.S1428L) alteration is located in exon 28 (coding exon 28) of the ADAMTS20 gene. This alteration results from a C to T substitution at nucleotide position 4283, causing the serine (S) at amino acid position 1428 to be replaced by a leucine (L). 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
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.4	D;D;D;.
REVEL	Benign	0.16
Sift	Benign	0.054	T;D;D;.
Sift4G	Uncertain	0.042	D;D;D;D
Vest4		0.37
MVP		0.83
MPC		0.040
ClinPred		0.30	T
GERP RS		3.8
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.43
SpliceAI score (max)		0.010		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: rs151062458; hg19: chr12-43819318; COSMIC: COSV67129816;