10-27509751-G-C

Variant names:

• chr10-27509751-G-C
• rs188397633
• NM_021252.5:c.69-124G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021252.5(RAB18):​c.69-124G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 787,834 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: RAB18 NM_021252.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.679
• Publications: 0 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=-0.82).
• BP6: Variant 10-27509751-G-C is Benign according to our data. Variant chr10-27509751-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1217698.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00401 (610/152158) while in subpopulation AFR AF = 0.0139 (576/41508). AF 95% confidence interval is 0.0129. There are 4 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB18	NM_021252.5	c.69-124G>C		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.69-124G>C		intron_variant	Intron 1 of 6	1	NM_021252.5	ENSP00000349415.7

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152040 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.00383

GnomAD4 exome AF: 0.000440 AC: 280 AN: 635676 Hom.: 5 AF XY: 0.000348 AC XY: 119 AN XY: 341498

African (AFR) AF: 0.0127 AC: 222 AN: 17528

American (AMR) AF: 0.000556 AC: 20 AN: 35968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20538

East Asian (EAS) AF: 0.00 AC: 0 AN: 33574

South Asian (SAS) AF: 0.0000153 AC: 1 AN: 65566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37208

Middle Eastern (MID) AF: 0.000385 AC: 1 AN: 2596

European-Non Finnish (NFE) AF: 0.0000103 AC: 4 AN: 389666

Other (OTH) AF: 0.000969 AC: 32 AN: 33032

GnomAD4 genome AF: 0.00401 AC: 610 AN: 152158 Hom.: 4 Cov.: 32 AF XY: 0.00389 AC XY: 289 AN XY: 74380

African (AFR) AF: 0.0139 AC: 576 AN: 41508

American (AMR) AF: 0.00163 AC: 25 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00449

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 24, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.1
DANN	Benign	0.51
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism

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: rs188397633; hg19: chr10-27798680;