rs61757480

Positions:

• chr4-72323087-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_014243.3(ADAMTS3):​c.872T>C​(p.Ile291Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ADAMTS3 NM_014243.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.75

Genes affected

ADAMTS3 (HGNC:219): (ADAM metallopeptidase with thrombospondin type 1 motif 3) 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 protease. This protease, a member of the procollagen aminopropeptidase subfamily of proteins, may play a role in the processing of type II fibrillar collagen in articular cartilage. [provided by RefSeq, Feb 2016]

ENSG00000250877 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 4-72323087-A-G is Pathogenic according to our data. Variant chr4-72323087-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 586988.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS3	NM_014243.3	c.872T>C	p.Ile291Thr	missense_variant	6/22	ENST00000286657.10	NP_055058.2
ADAMTS3	XM_011532421.2	c.815T>C	p.Ile272Thr	missense_variant	6/22		XP_011530723.1
ADAMTS3	XM_011532422.4	c.788T>C	p.Ile263Thr	missense_variant	6/22		XP_011530724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS3	ENST00000286657.10	c.872T>C	p.Ile291Thr	missense_variant	6/22	1	NM_014243.3	ENSP00000286657.4
ENSG00000250877	ENST00000503918.1	n.60A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460706 Hom.: 0 Cov.: 29 AF XY: 0.00000963 AC XY: 7 AN XY: 726716

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hennekam lymphangiectasia-lymphedema syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.78		Loss of stability (P = 0.0041);Loss of stability (P = 0.0041);
MVP		0.93
MPC		0.61
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.66
gMVP		0.75

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: rs61757480; hg19: chr4-73188804;