rs12935394

Variant names:

• chr16-77295093-C-A
• rs12935394
• NM_199355.4:c.2836G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-77295093-C-A
• chr16-77295093-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.2836G>T​(p.Ala946Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,614,064 control chromosomes in the GnomAD database, including 14,034 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1012 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13022 hom.)
• Consequence: ADAMTS18 NM_199355.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15
• 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=0.0026280582).
• BP6: Variant 16-77295093-C-A is Benign according to our data. Variant chr16-77295093-C-A is described in ClinVar as Benign. ClinVar VariationId is 1166617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 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.2836G>T	p.Ala946Ser	missense	Exon 19 of 23	NP_955387.1
	ADAMTS18	NM_001326358.2		c.2320G>T	p.Ala774Ser	missense	Exon 19 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.2836G>T	p.Ala946Ser	missense	Exon 19 of 23	ENSP00000282849.5
	ENSG00000260922	ENST00000648730.1		n.118-3797C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15480 AN: 152102 Hom.: 1012 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0782

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.135 AC: 33918 AN: 250998 AF XY: 0.134

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.130 AC: 190155 AN: 1461844 Hom.: 13022 Cov.: 33 AF XY: 0.130 AC XY: 94657 AN XY: 727218

African (AFR) AF: 0.0191 AC: 639 AN: 33480

American (AMR) AF: 0.209 AC: 9366 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5079 AN: 26136

East Asian (EAS) AF: 0.191 AC: 7589 AN: 39698

South Asian (SAS) AF: 0.133 AC: 11488 AN: 86254

European-Finnish (FIN) AF: 0.0819 AC: 4372 AN: 53406

Middle Eastern (MID) AF: 0.108 AC: 623 AN: 5768

European-Non Finnish (NFE) AF: 0.129 AC: 143022 AN: 1111988

Other (OTH) AF: 0.132 AC: 7977 AN: 60392

GnomAD4 genome AF: 0.102 AC: 15476 AN: 152220 Hom.: 1012 Cov.: 32 AF XY: 0.102 AC XY: 7615 AN XY: 74428

African (AFR) AF: 0.0227 AC: 944 AN: 41554

American (AMR) AF: 0.171 AC: 2610 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3470

East Asian (EAS) AF: 0.188 AC: 967 AN: 5148

South Asian (SAS) AF: 0.117 AC: 565 AN: 4826

European-Finnish (FIN) AF: 0.0782 AC: 830 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8517 AN: 68008

Other (OTH) AF: 0.119 AC: 252 AN: 2114

Alfa AF: 0.121 Hom.: 4266

Bravo AF: 0.108

TwinsUK AF: 0.134 AC: 497

ALSPAC AF: 0.123 AC: 474

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.131 AC: 1125

ExAC AF: 0.131 AC: 15912

Asia WGS AF: 0.139 AC: 481 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.133

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.95
DANN	Benign	0.63
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.7	N
PhyloP100		1.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.058
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
ClinPred		0.0051	T
GERP RS		3.3
Varity_R		0.032
gMVP		0.12
Mutation Taster		=99/1	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: rs12935394; hg19: chr16-77328990; COSMIC: COSV51420348; COSMIC: COSV51420348;