NM_021252.5:c.69-130T>A

Variant names:

• chr10-27509745-T-A
• rs11015829
• NM_021252.5:c.69-130T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021252.5(RAB18):​c.69-130T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 758,042 control chromosomes in the GnomAD database, including 80,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (14648 hom., cov: 32)
  • Exomes 𝑓: 0.46 (66213 hom.)
• Consequence: RAB18 NM_021252.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.89
• Publications: 3 publications found

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]

RAB18 Gene-Disease associations (from GenCC):

• Warburg micro syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Warburg micro syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-27509745-T-A is Benign according to our data. Variant chr10-27509745-T-A is described in ClinVar as [Benign]. Clinvar id is 668608.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB18	NM_021252.5	c.69-130T>A		intron_variant	Intron 1 of 6	ENST00000356940.11	NP_067075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB18	ENST00000356940.11	c.69-130T>A		intron_variant	Intron 1 of 6	1	NM_021252.5	ENSP00000349415.7

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65274 AN: 151898 Hom.: 14647 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.422

GnomAD4 exome AF: 0.456 AC: 276249 AN: 606026 Hom.: 66213 AF XY: 0.456 AC XY: 148784 AN XY: 326472

African (AFR) AF: 0.337 AC: 5659 AN: 16810

American (AMR) AF: 0.300 AC: 10521 AN: 35070

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 11436 AN: 20166

East Asian (EAS) AF: 0.145 AC: 4784 AN: 33084

South Asian (SAS) AF: 0.392 AC: 25239 AN: 64388

European-Finnish (FIN) AF: 0.492 AC: 17927 AN: 36442

Middle Eastern (MID) AF: 0.462 AC: 1169 AN: 2530

European-Non Finnish (NFE) AF: 0.506 AC: 184935 AN: 365542

Other (OTH) AF: 0.456 AC: 14579 AN: 31994

GnomAD4 genome AF: 0.429 AC: 65281 AN: 152016 Hom.: 14648 Cov.: 32 AF XY: 0.427 AC XY: 31713 AN XY: 74318

African (AFR) AF: 0.338 AC: 14013 AN: 41448

American (AMR) AF: 0.381 AC: 5825 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1975 AN: 3472

East Asian (EAS) AF: 0.167 AC: 868 AN: 5184

South Asian (SAS) AF: 0.375 AC: 1808 AN: 4818

European-Finnish (FIN) AF: 0.489 AC: 5163 AN: 10568

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34081 AN: 67934

Other (OTH) AF: 0.418 AC: 883 AN: 2110

Alfa AF: 0.464 Hom.: 2095

Bravo AF: 0.415

Asia WGS AF: 0.271 AC: 940 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.7
DANN	Benign	0.76
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11015829; hg19: chr10-27798674;