rs12935394

Positions:

• chr16-77295093-C-A
• chr16-77295093-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 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.

• 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, single submitter B:1
• Conservation: PhyloP100: 1.15

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]

LOC124903727 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1166617.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-77295093-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS18	NM_199355.4	c.2836G>T	p.Ala946Ser	missense_variant	19/23	ENST00000282849.10
LOC124903727	XR_007065122.1	n.181-3797C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.2836G>T	p.Ala946Ser	missense_variant	19/23	1	NM_199355.4	P1
	ENST00000648730.1	n.118-3797C>A		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.135 AC: 33918 AN: 250998 Hom.: 2718 AF XY: 0.134 AC XY: 18185 AN XY: 135650

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 SAS exome AF: 0.132

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

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.209

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0819

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.132

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

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0782

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.119

Alfa AF: 0.125 Hom.: 3157

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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: rs12935394; hg19: chr16-77328990; COSMIC: COSV51420348; COSMIC: COSV51420348;