rs2086310

Positions:

• chr5-5146222-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139056.4(ADAMTS16):​c.268C>G​(p.Pro90Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 1,613,920 control chromosomes in the GnomAD database, including 512,423 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 𝑓 0.75 (43634 hom., cov: 32)
  • Exomes 𝑓: 0.80 (468789 hom.)
• Consequence: ADAMTS16 NM_139056.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.404

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0635891E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS16	NM_139056.4	c.268C>G	p.Pro90Ala	missense_variant	3/23	ENST00000274181.7
ADAMTS16	XM_047416874.1	c.268C>G	p.Pro90Ala	missense_variant	3/22
ADAMTS16	XM_047416875.1	c.268C>G	p.Pro90Ala	missense_variant	3/20
ADAMTS16	NR_136935.2	n.406C>G		non_coding_transcript_exon_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS16	ENST00000274181.7	c.268C>G	p.Pro90Ala	missense_variant	3/23	2	NM_139056.4	P1
ADAMTS16	ENST00000511368.5	c.268C>G	p.Pro90Ala	missense_variant	3/11	1
ADAMTS16	ENST00000433402.2	n.268C>G		non_coding_transcript_exon_variant	3/20	1
	ENST00000514848.1	n.221-3851G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114281 AN: 151956 Hom.: 43608 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.784 AC: 195563 AN: 249488 Hom.: 77939 AF XY: 0.788 AC XY: 106669 AN XY: 135368

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.508

Gnomad SAS exome AF: 0.829

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.798 AC: 1166421 AN: 1461846 Hom.: 468789 Cov.: 66 AF XY: 0.800 AC XY: 581510 AN XY: 727226

Gnomad4 AFR exome AF: 0.617

Gnomad4 AMR exome AF: 0.885

Gnomad4 ASJ exome AF: 0.920

Gnomad4 EAS exome AF: 0.517

Gnomad4 SAS exome AF: 0.827

Gnomad4 FIN exome AF: 0.752

Gnomad4 NFE exome AF: 0.806

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.752 AC: 114347 AN: 152074 Hom.: 43634 Cov.: 32 AF XY: 0.750 AC XY: 55711 AN XY: 74324

Gnomad4 AFR AF: 0.632

Gnomad4 AMR AF: 0.849

Gnomad4 ASJ AF: 0.922

Gnomad4 EAS AF: 0.522

Gnomad4 SAS AF: 0.815

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.768

Alfa AF: 0.800 Hom.: 37074

Bravo AF: 0.752

TwinsUK AF: 0.802 AC: 2975

ALSPAC AF: 0.795 AC: 3065

ESP6500AA AF: 0.644 AC: 2623

ESP6500EA AF: 0.816 AC: 6831

ExAC AF: 0.775 AC: 93746

Asia WGS AF: 0.642 AC: 2236 AN: 3478

EpiCase AF: 0.816

EpiControl AF: 0.824

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.058
DANN	Benign	0.38
DEOGEN2	Benign	0.0052	.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.14	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	.;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.71	N;N
REVEL	Benign	0.012
Sift	Benign	1.0	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.0	B;B
Vest4		0.018
MPC		0.16
ClinPred		0.00030	T
GERP RS		-0.85
Varity_R		0.035
gMVP		0.12

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: rs2086310; hg19: chr5-5146335; COSMIC: COSV56986942;