16-77359310-G-C

Variant names:

• chr16-77359310-G-C
• rs2650907
• NM_199355.4:c.1322+8C>G

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.1322+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,610,402 control chromosomes in the GnomAD database, including 263,511 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21928 hom., cov: 32)
  • Exomes 𝑓: 0.57 (241583 hom.)
• Consequence: ADAMTS18 NM_199355.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003301
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.229
• Publications: 16 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, 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 (BayesDel_noAF=-0.82).
• BP6: Variant 16-77359310-G-C is Benign according to our data. Variant chr16-77359310-G-C is described in ClinVar as Benign. ClinVar VariationId is 1168654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 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.1322+8C>G		splice_region intron	N/A	NP_955387.1	Q8TE60-1
	ADAMTS18	NM_001326358.2		c.806+8C>G		splice_region intron	N/A	NP_001313287.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS18	ENST00000282849.10	TSL:1 MANE Select	c.1322+8C>G		splice_region intron	N/A	ENSP00000282849.5	Q8TE60-1
	ADAMTS18	ENST00000449265.2	TSL:2	n.*341+8C>G		splice_region intron	N/A	ENSP00000392540.2	B4DEX3

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80608 AN: 151936 Hom.: 21915 Cov.: 32

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.521

GnomAD2 exomes AF: 0.514 AC: 127533 AN: 248346 AF XY: 0.527

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.729

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.591

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.569 AC: 830346 AN: 1458348 Hom.: 241583 Cov.: 34 AF XY: 0.570 AC XY: 413409 AN XY: 725388

African (AFR) AF: 0.503 AC: 16835 AN: 33436

American (AMR) AF: 0.282 AC: 12572 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 19053 AN: 26088

East Asian (EAS) AF: 0.302 AC: 11961 AN: 39648

South Asian (SAS) AF: 0.562 AC: 48133 AN: 85704

European-Finnish (FIN) AF: 0.500 AC: 26668 AN: 53304

Middle Eastern (MID) AF: 0.507 AC: 2902 AN: 5728

European-Non Finnish (NFE) AF: 0.593 AC: 657809 AN: 1109646

Other (OTH) AF: 0.571 AC: 34413 AN: 60258

GnomAD4 genome AF: 0.530 AC: 80635 AN: 152054 Hom.: 21928 Cov.: 32 AF XY: 0.522 AC XY: 38821 AN XY: 74320

African (AFR) AF: 0.500 AC: 20726 AN: 41472

American (AMR) AF: 0.401 AC: 6124 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2508 AN: 3470

East Asian (EAS) AF: 0.340 AC: 1748 AN: 5148

South Asian (SAS) AF: 0.556 AC: 2685 AN: 4830

European-Finnish (FIN) AF: 0.489 AC: 5166 AN: 10562

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39819 AN: 67978

Other (OTH) AF: 0.516 AC: 1092 AN: 2116

Alfa AF: 0.584 Hom.: 8448

Bravo AF: 0.522

Asia WGS AF: 0.436 AC: 1522 AN: 3478

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
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.44
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs2650907; hg19: chr16-77393207; COSMIC: COSV51420677;