16-77284049-G-A

Position:

• chr16-77284049-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_199355.4(ADAMTS18):​c.3573C>T​(p.Phe1191Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000531 in 1,613,060 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (10 hom.)
• Consequence: ADAMTS18 NM_199355.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.00

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]

ENSG00000260922 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 16-77284049-G-A is Benign according to our data. Variant chr16-77284049-G-A is described in ClinVar as [Benign]. Clinvar id is 725691.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-77284049-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000829 (126/152062) while in subpopulation EAS AF= 0.0219 (113/5156). AF 95% confidence interval is 0.0186. There are 3 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS18	NM_199355.4	c.3573C>T	p.Phe1191Phe	synonymous_variant	23/23	ENST00000282849.10	NP_955387.1
ADAMTS18	NM_001326358.2	c.3057C>T	p.Phe1019Phe	synonymous_variant	23/23		NP_001313287.1
ADAMTS18	XM_047433672.1	c.2844C>T	p.Phe948Phe	synonymous_variant	19/19		XP_047289628.1
ADAMTS18	XM_047433673.1	c.2337C>T	p.Phe779Phe	synonymous_variant	17/17		XP_047289629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS18	ENST00000282849.10	c.3573C>T	p.Phe1191Phe	synonymous_variant	23/23	1	NM_199355.4	ENSP00000282849.5
ADAMTS18	ENST00000562332.1	c.94+5215C>T		intron_variant		2		ENSP00000454368.1
ENSG00000260922	ENST00000561672.1	n.74-5227G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000836 AC: 127 AN: 151948 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0221

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00162 AC: 406 AN: 250866 Hom.: 3 AF XY: 0.00155 AC XY: 210 AN XY: 135548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0211

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000500 AC: 731 AN: 1460998 Hom.: 10 Cov.: 30 AF XY: 0.000508 AC XY: 369 AN XY: 726874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000829 AC: 126 AN: 152062 Hom.: 3 Cov.: 31 AF XY: 0.000888 AC XY: 66 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0219

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.00577 AC: 21 AN: 3478

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.3
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147053635; hg19: chr16-77317946;