12-43383590-T-G

Position:

• chr12-43383590-T-G

Variant summary

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

The NM_025003.5(ADAMTS20):​c.4765A>C​(p.Asn1589His) 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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS20 NM_025003.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

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=0.12121689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS20	NM_025003.5	c.4765A>C	p.Asn1589His	missense_variant	31/39	ENST00000389420.8	NP_079279.3
ADAMTS20	XM_011538754.3	c.4768A>C	p.Asn1590His	missense_variant	31/39		XP_011537056.1
ADAMTS20	XM_017019979.2	c.3553A>C	p.Asn1185His	missense_variant	24/32		XP_016875468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS20	ENST00000389420.8	c.4765A>C	p.Asn1589His	missense_variant	31/39	1	NM_025003.5	ENSP00000374071	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jul 16, 2021

The c.4765A>C (p.N1589H) alteration is located in exon 31 (coding exon 31) of the ADAMTS20 gene. This alteration results from a A to C substitution at nucleotide position 4765, causing the asparagine (N) at amino acid position 1589 to be replaced by a histidine (H). 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	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.94
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.095
Sift	Benign	0.061	T
Sift4G	Benign	0.12	T
Vest4		0.11
MutPred		0.47		Gain of catalytic residue at P1586 (P = 0);
MVP		0.66
MPC		0.035
ClinPred		0.34	T
GERP RS		3.5
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-43777393;