12-43425576-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_025003.5(ADAMTS20):c.4222A>G(p.Ile1408Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,456,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ADAMTS20 NM_025003.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051596284).
• BP6: Variant 12-43425576-T-C is Benign according to our data. Variant chr12-43425576-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2595974.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS20	NM_025003.5	c.4222A>G	p.Ile1408Val	missense_variant	28/39	ENST00000389420.8
ADAMTS20	XM_011538754.3	c.4225A>G	p.Ile1409Val	missense_variant	28/39
ADAMTS20	XM_017019979.2	c.3010A>G	p.Ile1004Val	missense_variant	21/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS20	ENST00000389420.8	c.4222A>G	p.Ile1408Val	missense_variant	28/39	1	NM_025003.5	P1
ADAMTS20	ENST00000553158.5	c.4222A>G	p.Ile1408Val	missense_variant	28/29	5
ADAMTS20	ENST00000549670.5	c.1612A>G	p.Ile538Val	missense_variant	10/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247598 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1456108 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 12 AN XY: 724324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.8
Dann	Benign	0.83
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.54	T;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.43	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.33	N;N;N;.
REVEL	Benign	0.045
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	0.31	T;T;T;T
Vest4		0.14
MutPred		0.39		Gain of catalytic residue at P1404 (P = 0);.;Gain of catalytic residue at P1404 (P = 0);Gain of catalytic residue at P1404 (P = 0);
MVP		0.26
MPC		0.031
ClinPred		0.023	T
GERP RS		-1.1
gMVP		0.13

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: rs762796905; hg19: chr12-43819379;