rs587776875

Variant names:

• chr10-27533747-CAAG-C
• rs587776875
• NM_021252.5:c.277_279delAGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_021252.5(RAB18):​c.277_279delAGA​(p.Arg93del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB18 NM_021252.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.39
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P
• Warburg micro syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_021252.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021252.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-27533747-CAAG-C is Pathogenic according to our data. Variant chr10-27533747-CAAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30249.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	NM_021252.5	MANE Select	c.277_279delAGA	p.Arg93del	conservative_inframe_deletion	Exon 5 of 7	NP_067075.1	Q9NP72-1
	RAB18	NM_001256410.2		c.364_366delAGA	p.Arg122del	conservative_inframe_deletion	Exon 6 of 8	NP_001243339.1	Q9NP72-2
	RAB18	NM_001256411.2		c.277_279delAGA	p.Arg93del	conservative_inframe_deletion	Exon 5 of 6	NP_001243340.1	B7Z4P9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.277_279delAGA	p.Arg93del	conservative_inframe_deletion	Exon 5 of 7	ENSP00000349415.7	Q9NP72-1
	RAB18	ENST00000621805.6	TSL:1	c.364_366delAGA	p.Arg122del	conservative_inframe_deletion	Exon 6 of 8	ENSP00000478479.1	Q9NP72-2
	RAB18	ENST00000684501.1		c.277_279delAGA	p.Arg93del	conservative_inframe_deletion	Exon 5 of 6	ENSP00000507589.1	B7Z4P9

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Warburg micro syndrome 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=54/46	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587776875; hg19: chr10-27822676;