10-27504287-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000621805.5(RAB18):c.-83C>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0011 in 1,393,890 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: RAB18 ENST00000621805.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.67

Genes affected

RAB18 (HGNC:14244): (RAB18, member RAS oncogene family) The protein encoded by this gene is a member of a family of Ras-related small GTPases that regulate membrane trafficking in organelles and transport vesicles. Knockdown studies is zebrafish suggest that this protein may have a role in eye and brain development. Mutations in this gene are associated with Warburg micro syndrome type 3. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 10-27504287-C-A is Benign according to our data. Variant chr10-27504287-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 299810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00562 (856/152358) while in subpopulation AFR AF= 0.0198 (823/41582). AF 95% confidence interval is 0.0187. There are 11 homozygotes in gnomad4. There are 403 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB18	NM_021252.5			upstream_gene_variant		ENST00000356940.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB18	ENST00000356940.11			upstream_gene_variant		1	NM_021252.5	P1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152240 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00130 AC: 194 AN: 148774 Hom.: 1 AF XY: 0.00104 AC XY: 82 AN XY: 78774

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.000891

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000167

Gnomad OTH exome AF: 0.000688

GnomAD4 exome AF: 0.000547 AC: 679 AN: 1241532 Hom.: 7 Cov.: 18 AF XY: 0.000481 AC XY: 298 AN XY: 619476

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.000817

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000656

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000741

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152358 Hom.: 11 Cov.: 33 AF XY: 0.00541 AC XY: 403 AN XY: 74502

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00299 Hom.: 1

Bravo AF: 0.00617

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2019

- -

Warburg micro syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Benign	0.92

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: rs115326586; hg19: chr10-27793216;