rs3743749

Variant names:

• chr16-77289338-C-G
• rs3743749
• NM_199355.4:c.3476G>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199355.4(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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 NM_199355.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.17
• Publications: 22 publications found

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]

ADAMTS18 Gene-Disease associations (from GenCC):

• microcornea-myopic chorioretinal atrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ENSG00000260922 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1165095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ADAMTS18	NM_199355.4	c.3476G>C	p.Ser1159Thr	missense_variant	Exon 22 of 23	ENST00000282849.10	NP_955387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.3476G>C	p.Ser1159Thr	missense_variant	Exon 22 of 23	1	NM_199355.4	ENSP00000282849.5
ADAMTS18	ENST00000562332.1	c.20G>C	p.Ser7Thr	missense_variant	Exon 1 of 2	2		ENSP00000454368.1
ENSG00000260922	ENST00000561672.1	n.136C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
ENSG00000260922	ENST00000648730.1	n.-1C>G		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

GnomAD2 exomes AF: 0.148 AC: 37226 AN: 251258 AF XY: 0.150

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 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

African (AFR) AF: 0.196 AC: 6573 AN: 33478

American (AMR) AF: 0.109 AC: 4870 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3787 AN: 26136

East Asian (EAS) AF: 0.204 AC: 8095 AN: 39696

South Asian (SAS) AF: 0.155 AC: 13363 AN: 86258

European-Finnish (FIN) AF: 0.115 AC: 6161 AN: 53416

Middle Eastern (MID) AF: 0.187 AC: 1079 AN: 5768

European-Non Finnish (NFE) AF: 0.143 AC: 158940 AN: 1111960

Other (OTH) AF: 0.153 AC: 9254 AN: 60392

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

African (AFR) AF: 0.199 AC: 8237 AN: 41462

American (AMR) AF: 0.125 AC: 1907 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1081 AN: 5150

South Asian (SAS) AF: 0.167 AC: 803 AN: 4814

European-Finnish (FIN) AF: 0.116 AC: 1230 AN: 10608

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10075 AN: 67982

Other (OTH) AF: 0.152 AC: 322 AN: 2116

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		3.2
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
PromoterAI		0.022	Neutral
Varity_R		0.16
gMVP		0.31
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

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