10-27504376-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021252.5(RAB18):c.7G>C(p.Glu3Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAB18 NM_021252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22181627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB18	NM_021252.5	c.7G>C	p.Glu3Gln	missense_variant	1/7	ENST00000356940.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB18	ENST00000356940.11	c.7G>C	p.Glu3Gln	missense_variant	1/7	1	NM_021252.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422944 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The c.7G>C (p.E3Q) 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 7, causing the glutamic acid (E) at amino acid position 3 to be replaced by a glutamine (Q). 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	Benign	0.21
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.077
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.47	N;.;N;.;N
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N;.;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.040	D;.;T;T;.
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.031	.;.;B;.;.
Vest4		0.46
MutPred		0.34		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP		0.59
MPC		0.44
ClinPred		0.55	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.43
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1445127484; hg19: chr10-27793305;