NM_021252.5:c.619T>C

Variant names:

• chr10-27538049-T-C
• rs387906833
• NM_021252.5:c.619T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_021252.5(RAB18):​c.619T>C​(p.Ter207Glnext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAB18 NM_021252.5 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.65
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_021252.5 Downstream stopcodon found after 228 codons.
• PP5: Variant 10-27538049-T-C is Pathogenic according to our data. Variant chr10-27538049-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30250.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	NM_021252.5	MANE Select	c.619T>C	p.Ter207Glnext*?	stop_lost	Exon 7 of 7	NP_067075.1
	RAB18	NM_001256410.2		c.706T>C	p.Ter236Glnext*?	stop_lost	Exon 8 of 8	NP_001243339.1
	RAB18	NM_001256412.2		c.427T>C	p.Ter143Glnext*?	stop_lost	Exon 5 of 5	NP_001243341.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.619T>C	p.Ter207Glnext*?	stop_lost	Exon 7 of 7	ENSP00000349415.7
	RAB18	ENST00000621805.6	TSL:1	c.706T>C	p.Ter236Glnext*?	stop_lost	Exon 8 of 8	ENSP00000478479.1
	RAB18	ENST00000375802.7	TSL:5	c.484T>C	p.Ter162Glnext*?	stop_lost	Exon 5 of 5	ENSP00000364960.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251268 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Warburg micro syndrome 3 Pathogenic:2 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Apr 08, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.88
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.7
Vest4		0.30
GERP RS		6.2
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs387906833; hg19: chr10-27826978; COSMIC: COSV63613746; COSMIC: COSV63613746;