NM_199355.4:c.571T>C

Variant names:

• chr16-77367648-A-G
• rs11643211
• NM_199355.4:c.571T>C

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.571T>C​(p.Tyr191His) variant causes a missense change. The variant allele was found at a frequency of 0.272 in 1,613,874 control chromosomes in the GnomAD database, including 66,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y191Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6697 hom., cov: 32)
  • Exomes 𝑓: 0.27 (59423 hom.)
• Consequence: ADAMTS18 NM_199355.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.16
• Publications: 31 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5203824E-4).
• BP6: Variant 16-77367648-A-G is Benign according to our data. Variant chr16-77367648-A-G is described in ClinVar as Benign. ClinVar VariationId is 803274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	NM_199355.4	MANE Select	c.571T>C	p.Tyr191His	missense	Exon 4 of 23	NP_955387.1
	ADAMTS18	NM_001326358.2		c.51T>C	p.Thr17Thr	synonymous	Exon 4 of 23	NP_001313287.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.571T>C	p.Tyr191His	missense	Exon 4 of 23	ENSP00000282849.5
	ADAMTS18	ENST00000562345.1	TSL:5	c.313T>C	p.Tyr105His	missense	Exon 2 of 3	ENSP00000457395.1
	ADAMTS18	ENST00000449265.2	TSL:2	n.571T>C		non_coding_transcript_exon	Exon 4 of 8	ENSP00000392540.2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43142 AN: 151894 Hom.: 6679 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.326 AC: 82059 AN: 251388 AF XY: 0.315

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.271 AC: 395856 AN: 1461862 Hom.: 59423 Cov.: 46 AF XY: 0.270 AC XY: 196678 AN XY: 727238

African (AFR) AF: 0.253 AC: 8469 AN: 33480

American (AMR) AF: 0.565 AC: 25258 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4913 AN: 26136

East Asian (EAS) AF: 0.624 AC: 24784 AN: 39700

South Asian (SAS) AF: 0.295 AC: 25486 AN: 86256

European-Finnish (FIN) AF: 0.262 AC: 13998 AN: 53418

Middle Eastern (MID) AF: 0.280 AC: 1617 AN: 5768

European-Non Finnish (NFE) AF: 0.247 AC: 274608 AN: 1111990

Other (OTH) AF: 0.277 AC: 16723 AN: 60396

GnomAD4 genome AF: 0.284 AC: 43182 AN: 152012 Hom.: 6697 Cov.: 32 AF XY: 0.289 AC XY: 21445 AN XY: 74302

African (AFR) AF: 0.252 AC: 10448 AN: 41450

American (AMR) AF: 0.437 AC: 6673 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3470

East Asian (EAS) AF: 0.578 AC: 2970 AN: 5140

South Asian (SAS) AF: 0.299 AC: 1443 AN: 4820

European-Finnish (FIN) AF: 0.257 AC: 2713 AN: 10572

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17293 AN: 67970

Other (OTH) AF: 0.325 AC: 685 AN: 2106

Alfa AF: 0.270 Hom.: 21084

Bravo AF: 0.300

TwinsUK AF: 0.221 AC: 819

ALSPAC AF: 0.259 AC: 998

ESP6500AA AF: 0.260 AC: 1145

ESP6500EA AF: 0.249 AC: 2138

ExAC AF: 0.316 AC: 38333

Asia WGS AF: 0.445 AC: 1543 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Microcornea-myopic chorioretinal atrophy Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.00025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.43	T
Sift4G	Benign	0.27	T
Polyphen		0.60	P
Vest4		0.096
ClinPred		0.030	T
GERP RS		4.7
Varity_R		0.30
gMVP		0.53
Mutation Taster		=46/54	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: rs11643211; hg19: chr16-77401545; COSMIC: COSV51420005;