rs3743749

Positions:

• chr16-77289338-C-G
• chr16-77289338-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000282849.10(ADAMTS18):​c.3476G>C​(p.Ser1159Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,908 control chromosomes in the GnomAD database, including 18,015 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1159N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2052 hom., cov: 32)
  • Exomes 𝑓: 0.15 (15963 hom.)
• Consequence: ADAMTS18 ENST00000282849.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.17

Genes affected

ADAMTS18 (HGNC:17110): (ADAM metallopeptidase with thrombospondin type 1 motif 18) 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 regulate hemostatic balance and function as a tumor suppressor. Mutations in this gene may be associated with microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) and cone-rod dystrophy in human patients. [provided by RefSeq, May 2016]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010043979).
• BP6: Variant 16-77289338-C-G is Benign according to our data. Variant chr16-77289338-C-G is described in ClinVar as [Benign]. Clinvar id is 1165095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-77289338-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS18	NM_199355.4	c.3476G>C	p.Ser1159Thr	missense_variant	22/23	ENST00000282849.10	NP_955387.1
LOC124903727	XR_007065122.1	n.63C>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.3476G>C	p.Ser1159Thr	missense_variant	22/23	1	NM_199355.4	ENSP00000282849	P1
	ENST00000561672.1	n.136C>G		non_coding_transcript_exon_variant	2/3	2
ADAMTS18	ENST00000562332.1	c.23G>C	p.Ser8Thr	missense_variant	1/2	2		ENSP00000454368
	ENST00000648730.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24331 AN: 151960 Hom.: 2044 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.148 AC: 37226 AN: 251258 Hom.: 2920 AF XY: 0.150 AC XY: 20372 AN XY: 135788

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.145 AC: 212122 AN: 1461828 Hom.: 15963 Cov.: 33 AF XY: 0.146 AC XY: 106276 AN XY: 727226

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.160 AC: 24354 AN: 152080 Hom.: 2052 Cov.: 32 AF XY: 0.159 AC XY: 11788 AN XY: 74370

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.152

Alfa AF: 0.144 Hom.: 1319

Bravo AF: 0.161

TwinsUK AF: 0.141 AC: 524

ALSPAC AF: 0.145 AC: 558

ESP6500AA AF: 0.210 AC: 923

ESP6500EA AF: 0.142 AC: 1217

ExAC AF: 0.150 AC: 18185

Asia WGS AF: 0.234 AC: 812 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.151

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.059	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.086
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.018	D
Polyphen		0.12	B
Vest4		0.084
ClinPred		0.020	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.31

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: rs3743749; hg19: chr16-77323235; COSMIC: COSV51413979;