NM_021252.5:c.50G>C

Variant names:

• chr10-27504419-G-C
• rs761909429
• NM_021252.5:c.50G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021252.5(RAB18):​c.50G>C​(p.Ser17Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,416,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAB18 NM_021252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• Publications: 1 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

LOC124902399 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB18	NM_021252.5	c.50G>C	p.Ser17Thr	missense_variant	Exon 1 of 7	ENST00000356940.11	NP_067075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB18	ENST00000356940.11	c.50G>C	p.Ser17Thr	missense_variant	Exon 1 of 7	1	NM_021252.5	ENSP00000349415.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 178594 AF XY: 0.0000212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1416972 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700052

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32982

American (AMR) AF: 0.00 AC: 0 AN: 36606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.0000525 AC: 2 AN: 38076

South Asian (SAS) AF: 0.00 AC: 0 AN: 80504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088722

Other (OTH) AF: 0.0000170 AC: 1 AN: 58826

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000042), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000862 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50G>C (p.S17T) alteration is located in exon 1 (coding exon 1) of the RAB18 gene. This alteration results from a G to C substitution at nucleotide position 50, causing the serine (S) at amino acid position 17 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;D;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.6	L;.;L;.;L
PhyloP100		4.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N;.;N;N;.
REVEL	Uncertain	0.46
Sift	Benign	0.060	T;.;D;D;.
Sift4G	Uncertain	0.046	D;T;T;T;T
Polyphen		0.83	.;.;P;.;.
Vest4		0.56
MutPred		0.76		Loss of glycosylation at S17 (P = 0.0676);Loss of glycosylation at S17 (P = 0.0676);Loss of glycosylation at S17 (P = 0.0676);Loss of glycosylation at S17 (P = 0.0676);Loss of glycosylation at S17 (P = 0.0676);
MVP		0.71
MPC		0.47
ClinPred		0.70	D
GERP RS		4.6
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.85
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs761909429; hg19: chr10-27793348; COSMIC: COSV105914915; COSMIC: COSV105914915;