chr16-77291428-G-T

Variant names:

• chr16-77291428-G-T
• rs35478105
• NM_199355.4:c.3240C>A

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.3240C>A​(p.Ser1080Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,613,778 control chromosomes in the GnomAD database, including 172,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. S1080I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (11676 hom., cov: 32)
  • Exomes 𝑓: 0.46 (161158 hom.)
• Consequence: ADAMTS18 NM_199355.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.508
• Publications: 28 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=1.0391632E-4).
• BP6: Variant 16-77291428-G-T is Benign according to our data. Variant chr16-77291428-G-T is described in ClinVar as Benign. ClinVar VariationId is 1166169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.489 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.3240C>A	p.Ser1080Arg	missense	Exon 21 of 23	NP_955387.1
	ADAMTS18	NM_001326358.2		c.2724C>A	p.Ser908Arg	missense	Exon 21 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.3240C>A	p.Ser1080Arg	missense	Exon 21 of 23	ENSP00000282849.5
	ENSG00000260922	ENST00000648730.1		n.117+1973G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53352 AN: 151904 Hom.: 11682 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.378 AC: 94942 AN: 251316 AF XY: 0.387

Gnomad AFR exome AF: 0.0982

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.457 AC: 668527 AN: 1461756 Hom.: 161158 Cov.: 59 AF XY: 0.455 AC XY: 330570 AN XY: 727204

African (AFR) AF: 0.0980 AC: 3281 AN: 33480

American (AMR) AF: 0.226 AC: 10097 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12961 AN: 26136

East Asian (EAS) AF: 0.129 AC: 5105 AN: 39700

South Asian (SAS) AF: 0.312 AC: 26942 AN: 86256

European-Finnish (FIN) AF: 0.503 AC: 26840 AN: 53396

Middle Eastern (MID) AF: 0.384 AC: 2215 AN: 5768

European-Non Finnish (NFE) AF: 0.499 AC: 555184 AN: 1111900

Other (OTH) AF: 0.429 AC: 25902 AN: 60396

GnomAD4 genome AF: 0.351 AC: 53337 AN: 152022 Hom.: 11676 Cov.: 32 AF XY: 0.346 AC XY: 25700 AN XY: 74308

African (AFR) AF: 0.111 AC: 4586 AN: 41490

American (AMR) AF: 0.301 AC: 4598 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1708 AN: 3468

East Asian (EAS) AF: 0.129 AC: 667 AN: 5158

South Asian (SAS) AF: 0.320 AC: 1541 AN: 4812

European-Finnish (FIN) AF: 0.501 AC: 5280 AN: 10542

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33518 AN: 67952

Other (OTH) AF: 0.372 AC: 785 AN: 2110

Alfa AF: 0.432 Hom.: 43522

Bravo AF: 0.327

TwinsUK AF: 0.497 AC: 1843

ALSPAC AF: 0.507 AC: 1955

ESP6500AA AF: 0.119 AC: 525

ESP6500EA AF: 0.495 AC: 4260

ExAC AF: 0.377 AC: 45719

Asia WGS AF: 0.180 AC: 629 AN: 3478

EpiCase AF: 0.497

EpiControl AF: 0.491

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.39	N
PhyloP100		-0.51
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.036
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.013	D
Polyphen		0.19	B
Vest4		0.18
MutPred		0.29		Gain of MoRF binding (P = 0.0271)
ClinPred		0.042	T
GERP RS		-4.8
Varity_R		0.13
gMVP		0.47
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs35478105; hg19: chr16-77325325; COSMIC: COSV51399882; COSMIC: COSV51399882;