5-5140472-A-C

Position:

• chr5-5140472-A-C

Variant summary

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

The NM_139056.4(ADAMTS16):​c.5A>C​(p.Lys2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,360,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ADAMTS16 NM_139056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.138

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=0.114878565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS16	NM_139056.4	c.5A>C	p.Lys2Thr	missense_variant	1/23	ENST00000274181.7	NP_620687.2
ADAMTS16	XM_047416874.1	c.5A>C	p.Lys2Thr	missense_variant	1/22		XP_047272830.1
ADAMTS16	XM_047416875.1	c.5A>C	p.Lys2Thr	missense_variant	1/20		XP_047272831.1
ADAMTS16	NR_136935.2	n.143A>C		non_coding_transcript_exon_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS16	ENST00000274181.7	c.5A>C	p.Lys2Thr	missense_variant	1/23	2	NM_139056.4	ENSP00000274181.7
ADAMTS16	ENST00000511368.5	c.5A>C	p.Lys2Thr	missense_variant	1/11	1		ENSP00000421631.1
ADAMTS16	ENST00000433402.2	n.5A>C		non_coding_transcript_exon_variant	1/20	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1360128 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 671566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000914

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.: 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

Sep 26, 2024

The c.5A>C (p.K2T) alteration is located in exon 1 (coding exon 1) of the ADAMTS16 gene. This alteration results from a A to C substitution at nucleotide position 5, causing the lysine (K) at amino acid position 2 to be replaced by a threonine (T). 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	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0095	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.018
Sift	Pathogenic	0.0	D;D
Polyphen		0.12	B;B
Vest4		0.13
MutPred		0.32		Gain of phosphorylation at K2 (P = 0.0119);Gain of phosphorylation at K2 (P = 0.0119);
MVP		0.46
MPC		0.20
ClinPred		0.039	T
GERP RS		-0.32
Varity_R		0.12
gMVP		0.50

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: rs1473441083; hg19: chr5-5140585;