chr10-27532527-G-T

Variant names:

• chr10-27532527-G-T
• rs770109036
• NM_021252.5:c.207G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021252.5(RAB18):​c.207G>T​(p.Arg69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R69R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAB18 NM_021252.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

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.207G>T	p.Arg69Ser	missense	Exon 4 of 7	NP_067075.1
	RAB18	NM_001256410.2		c.294G>T	p.Arg98Ser	missense	Exon 5 of 8	NP_001243339.1
	RAB18	NM_001256411.2		c.207G>T	p.Arg69Ser	missense	Exon 4 of 6	NP_001243340.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.207G>T	p.Arg69Ser	missense	Exon 4 of 7	ENSP00000349415.7
	RAB18	ENST00000621805.6	TSL:1	c.294G>T	p.Arg98Ser	missense	Exon 5 of 8	ENSP00000478479.1
	RAB18	ENST00000684501.1		c.207G>T	p.Arg69Ser	missense	Exon 4 of 6	ENSP00000507589.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453432 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723518

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105332

Other (OTH) AF: 0.00 AC: 0 AN: 60068

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.34
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.097	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Gain of disorder (P = 0.074)
MVP		0.99
MPC		0.55
ClinPred		0.98	D
GERP RS		-0.90
PromoterAI		-0.013	Neutral
Varity_R		0.90
gMVP		0.81
Mutation Taster		=38/62	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

Other links and lift over

dbSNP: rs770109036; hg19: chr10-27821456;