NM_021252.5:c.85A>C

Variant names:

• chr10-27509891-A-C
• rs2138970903
• NM_021252.5:c.85A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021252.5(RAB18):​c.85A>C​(p.Thr29Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB18 NM_021252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58
• 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: Labcorp Genetics (formerly Invitae), G2P
• Warburg micro syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

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.85A>C	p.Thr29Pro	missense	Exon 2 of 7	NP_067075.1	Q9NP72-1
	RAB18	NM_001256410.2		c.85A>C	p.Thr29Pro	missense	Exon 2 of 8	NP_001243339.1	Q9NP72-2
	RAB18	NM_001256411.2		c.85A>C	p.Thr29Pro	missense	Exon 2 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.85A>C	p.Thr29Pro	missense	Exon 2 of 7	ENSP00000349415.7	Q9NP72-1
	RAB18	ENST00000621805.6	TSL:1	c.85A>C	p.Thr29Pro	missense	Exon 2 of 8	ENSP00000478479.1	Q9NP72-2
	RAB18	ENST00000684501.1		c.85A>C	p.Thr29Pro	missense	Exon 2 of 6	ENSP00000507589.1	B7Z4P9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
PhyloP100		5.6
Varity_R		0.96
gMVP		0.96
Mutation Taster		=36/64	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2138970903; hg19: chr10-27798820;