NM_199355.4:c.2931G>A

Variant names:

• chr16-77294998-C-T
• rs12935229
• NM_199355.4:c.2931G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_199355.4(ADAMTS18):​c.2931G>A​(p.Val977Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,614,014 control chromosomes in the GnomAD database, including 14,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V977V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (1019 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13005 hom.)
• Consequence: ADAMTS18 NM_199355.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.960
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• inherited retinal dystrophy

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

ENSG00000260922 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-77294998-C-T is Benign according to our data. Variant chr16-77294998-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	NM_199355.4	MANE Select	c.2931G>A	p.Val977Val	synonymous	Exon 19 of 23	NP_955387.1	Q8TE60-1
	ADAMTS18	NM_001326358.2		c.2415G>A	p.Val805Val	synonymous	Exon 19 of 23	NP_001313287.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.2931G>A	p.Val977Val	synonymous	Exon 19 of 23	ENSP00000282849.5	Q8TE60-1
	ENSG00000260922	ENST00000648730.1		n.118-3892C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15490 AN: 152088 Hom.: 1018 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: 0.188

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0783

Gnomad MID AF: 0.0673

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.135 AC: 33896 AN: 251280 AF XY: 0.134

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0770

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.130 AC: 190097 AN: 1461806 Hom.: 13005 Cov.: 33 AF XY: 0.130 AC XY: 94645 AN XY: 727200

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

American (AMR) AF: 0.208 AC: 9305 AN: 44714

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

East Asian (EAS) AF: 0.191 AC: 7580 AN: 39694

South Asian (SAS) AF: 0.133 AC: 11489 AN: 86256

European-Finnish (FIN) AF: 0.0819 AC: 4373 AN: 53406

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

European-Non Finnish (NFE) AF: 0.129 AC: 143028 AN: 1111958

Other (OTH) AF: 0.132 AC: 7981 AN: 60394

GnomAD4 genome AF: 0.102 AC: 15488 AN: 152208 Hom.: 1019 Cov.: 32 AF XY: 0.102 AC XY: 7628 AN XY: 74422

African (AFR) AF: 0.0227 AC: 944 AN: 41548

American (AMR) AF: 0.171 AC: 2610 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3470

East Asian (EAS) AF: 0.189 AC: 976 AN: 5164

South Asian (SAS) AF: 0.117 AC: 563 AN: 4818

European-Finnish (FIN) AF: 0.0783 AC: 830 AN: 10600

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.125 AC: 8520 AN: 68018

Other (OTH) AF: 0.119 AC: 252 AN: 2112

Alfa AF: 0.121 Hom.: 3973

Bravo AF: 0.108

Asia WGS AF: 0.139 AC: 481 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.133

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs12935229; hg19: chr16-77328895; COSMIC: COSV99271418; COSMIC: COSV99271418;