NM_014244.5:c.733G>T

Variant names:

• chr5-179207671-C-A
• rs398829
• NM_014244.5:c.733G>T

Variant summary

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

The NM_014244.5(ADAMTS2):​c.733G>T​(p.Val245Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. V245I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• Publications: 0 publications found

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) 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 procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

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=0.09067148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.733G>T	p.Val245Phe	missense_variant	Exon 4 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.733G>T	p.Val245Phe	missense_variant	Exon 4 of 11		NP_067610.1
ADAMTS2	XM_047417895.1	c.238G>T	p.Val80Phe	missense_variant	Exon 3 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.-150G>T		5_prime_UTR_variant	Exon 2 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.733G>T	p.Val245Phe	missense_variant	Exon 4 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.733G>T	p.Val245Phe	missense_variant	Exon 4 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.733G>T	p.Val245Phe	missense_variant	Exon 4 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.733G>T		non_coding_transcript_exon_variant	Exon 4 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461048 Hom.: 0 Cov.: 64 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.2
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.065	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L;.;L
PhyloP100		-0.20
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.040
Sift	Benign	0.59	T;.;T
Sift4G	Benign	0.40	T;.;T
Polyphen		0.39	B;.;P
Vest4		0.21
MutPred		0.22		Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);
MVP		0.40
MPC		0.54
ClinPred		0.13	T
GERP RS		1.2
Varity_R		0.074
gMVP		0.53
Mutation Taster		=90/10	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: rs398829; hg19: chr5-178634672;