4-72283311-G-T

Variant names:

• chr4-72283311-G-T
• rs35780102
• NM_014243.3:c.3443C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014243.3(ADAMTS3):​c.3443C>A​(p.Pro1148Gln) 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. 16/22 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. P1148L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS3 NM_014243.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 1 publications found

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]

ADAMTS3 Gene-Disease associations (from GenCC):

• hennekam lymphangiectasia-lymphedema syndrome 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21885628).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014243.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS3	NM_014243.3	MANE Select	c.3443C>A	p.Pro1148Gln	missense	Exon 22 of 22	NP_055058.2	O15072

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS3	ENST00000286657.10	TSL:1 MANE Select	c.3443C>A	p.Pro1148Gln	missense	Exon 22 of 22	ENSP00000286657.4	O15072

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.12
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.019	D
Polyphen		0.97	D
Vest4		0.11
MutPred		0.19		Gain of solvent accessibility (P = 0.0044)
MVP		0.72
MPC		0.11
ClinPred		0.16	T
GERP RS		2.5
Varity_R		0.042
gMVP		0.28
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs35780102; hg19: chr4-73149028;