5-5140734-C-T

Variant summary

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

The NM_139056.4(ADAMTS16):c.143C>T(p.Pro48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ADAMTS16 NM_139056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.117

Genes affected

ADAMTS16 (HGNC:17108): (ADAM metallopeptidase with thrombospondin type 1 motif 16) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members 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 protein, which may inhibit chondrosarcoma cell proliferation and migration. This gene may regulate blood pressure. [provided by RefSeq, May 2016]

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=0.09356484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS16	NM_139056.4	c.143C>T	p.Pro48Leu	missense_variant	2/23	ENST00000274181.7
ADAMTS16	XM_047416874.1	c.143C>T	p.Pro48Leu	missense_variant	2/22
ADAMTS16	XM_047416875.1	c.143C>T	p.Pro48Leu	missense_variant	2/20
ADAMTS16	NR_136935.2	n.281C>T		non_coding_transcript_exon_variant	2/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS16	ENST00000274181.7	c.143C>T	p.Pro48Leu	missense_variant	2/23	2	NM_139056.4	P1
ADAMTS16	ENST00000511368.5	c.143C>T	p.Pro48Leu	missense_variant	2/11	1
ADAMTS16	ENST00000433402.2	n.143C>T		non_coding_transcript_exon_variant	2/20	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417452 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 701066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000260

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Nov 08, 2022

The c.143C>T (p.P48L) alteration is located in exon 2 (coding exon 2) of the ADAMTS16 gene. This alteration results from a C to T substitution at nucleotide position 143, causing the proline (P) at amino acid position 48 to be replaced by a leucine (L). 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
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.3
Dann	Benign	0.86
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.028
Sift	Benign	0.67	T;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.0050	B;B
Vest4		0.21
MutPred		0.45		Loss of glycosylation at P48 (P = 0.0048);Loss of glycosylation at P48 (P = 0.0048);
MVP		0.41
MPC		0.16
ClinPred		0.033	T
GERP RS		1.5
Varity_R		0.025
gMVP		0.18

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: rs1407733559; hg19: chr5-5140847;