5-5182129-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139056.4(ADAMTS16):c.587A>G(p.Gln196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,614,012 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: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: ADAMTS16 NM_139056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.606

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040360093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS16	NM_139056.4	c.587A>G	p.Gln196Arg	missense_variant	4/23	ENST00000274181.7
ADAMTS16	XM_047416874.1	c.587A>G	p.Gln196Arg	missense_variant	4/22
ADAMTS16	XM_047416875.1	c.587A>G	p.Gln196Arg	missense_variant	4/20
ADAMTS16	NR_136935.2	n.725A>G		non_coding_transcript_exon_variant	4/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS16	ENST00000274181.7	c.587A>G	p.Gln196Arg	missense_variant	4/23	2	NM_139056.4	P1
ADAMTS16	ENST00000511368.5	c.587A>G	p.Gln196Arg	missense_variant	4/11	1
ADAMTS16	ENST00000433402.2	n.587A>G		non_coding_transcript_exon_variant	4/20	1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000747 AC: 186 AN: 248980 Hom.: 0 AF XY: 0.000747 AC XY: 101 AN XY: 135232

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00677

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000426 AC: 622 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.000428 AC XY: 311 AN XY: 727158

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000777 Hom.: 2

Bravo AF: 0.000608

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000729 AC: 6

ExAC AF: 0.000422 AC: 51

EpiCase AF: 0.000218

EpiControl AF: 0.000652

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 16, 2021

The c.587A>G (p.Q196R) alteration is located in exon 4 (coding exon 4) of the ADAMTS16 gene. This alteration results from a A to G substitution at nucleotide position 587, causing the glutamine (Q) at amino acid position 196 to be replaced by an arginine (R). 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	0.058
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.10
Dann	Benign	0.57
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.045
Sift	Benign	0.33	T;T
Sift4G	Benign	0.10	T;D
Polyphen		0.0	B;B
Vest4		0.060
MVP		0.20
MPC		0.18
ClinPred		0.0088	T
GERP RS		-9.8
Varity_R		0.032
gMVP		0.30

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: rs72647742; hg19: chr5-5182242; COSMIC: COSV99068526;