chr10-27532452-T-A

Variant names:

• chr10-27532452-T-A
• rs3765133
• NM_021252.5:c.187-55T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021252.5(RAB18):​c.187-55T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,276,490 control chromosomes in the GnomAD database, including 3,993 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (314 hom., cov: 32)
  • Exomes 𝑓: 0.028 (3679 hom.)
• Consequence: RAB18 NM_021252.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.449
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021252.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	NM_021252.5	MANE Select	c.187-55T>A		intron	N/A	NP_067075.1
	RAB18	NM_001256410.2		c.274-55T>A		intron	N/A	NP_001243339.1
	RAB18	NM_001256411.2		c.187-55T>A		intron	N/A	NP_001243340.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.187-55T>A		intron	N/A	ENSP00000349415.7
	RAB18	ENST00000621805.6	TSL:1	c.274-55T>A		intron	N/A	ENSP00000478479.1
	RAB18	ENST00000682138.1		n.5667T>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3535 AN: 152034 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0276 AC: 31025 AN: 1124338 Hom.: 3679 AF XY: 0.0302 AC XY: 17375 AN XY: 574978

African (AFR) AF: 0.00167 AC: 44 AN: 26272

American (AMR) AF: 0.0502 AC: 2178 AN: 43420

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 375 AN: 23860

East Asian (EAS) AF: 0.378 AC: 14244 AN: 37672

South Asian (SAS) AF: 0.116 AC: 9047 AN: 77806

European-Finnish (FIN) AF: 0.0316 AC: 1580 AN: 50002

Middle Eastern (MID) AF: 0.0203 AC: 75 AN: 3686

European-Non Finnish (NFE) AF: 0.00242 AC: 1965 AN: 812676

Other (OTH) AF: 0.0310 AC: 1517 AN: 48944

GnomAD4 genome AF: 0.0232 AC: 3530 AN: 152152 Hom.: 314 Cov.: 32 AF XY: 0.0283 AC XY: 2108 AN XY: 74394

African (AFR) AF: 0.00277 AC: 115 AN: 41554

American (AMR) AF: 0.0338 AC: 517 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.304 AC: 1570 AN: 5172

South Asian (SAS) AF: 0.141 AC: 681 AN: 4826

European-Finnish (FIN) AF: 0.0318 AC: 337 AN: 10596

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 67936

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0112 Hom.: 8

Bravo AF: 0.0228

Asia WGS AF: 0.195 AC: 673 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		-0.45
PromoterAI		0.0096	Neutral
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: rs3765133; hg19: chr10-27821381; COSMIC: COSV63613255;