NM_021252.5:c.592G>A

Variant names:

• chr10-27538022-G-A
• rs11015859
• NM_021252.5:c.592G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021252.5(RAB18):​c.592G>A​(p.Ala198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,614,104 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (182 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (149 hom.)
• Consequence: RAB18 NM_021252.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.37
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001650244).
• BP6: Variant 10-27538022-G-A is Benign according to our data. Variant chr10-27538022-G-A is described in ClinVar as Benign. ClinVar VariationId is 130059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

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.592G>A	p.Ala198Thr	missense	Exon 7 of 7	NP_067075.1	Q9NP72-1
	RAB18	NM_001256410.2		c.679G>A	p.Ala227Thr	missense	Exon 8 of 8	NP_001243339.1	Q9NP72-2
	RAB18	NM_001256412.2		c.400G>A	p.Ala134Thr	missense	Exon 5 of 5	NP_001243341.1	Q9NP72-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.592G>A	p.Ala198Thr	missense	Exon 7 of 7	ENSP00000349415.7	Q9NP72-1
	RAB18	ENST00000621805.6	TSL:1	c.679G>A	p.Ala227Thr	missense	Exon 8 of 8	ENSP00000478479.1	Q9NP72-2
	RAB18	ENST00000375802.7	TSL:5	c.457G>A	p.Ala153Thr	missense	Exon 5 of 5	ENSP00000364960.3	Q5W0J0

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4054 AN: 152158 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00729 AC: 1833 AN: 251300 AF XY: 0.00542

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00284 AC: 4148 AN: 1461828 Hom.: 149 Cov.: 31 AF XY: 0.00246 AC XY: 1787 AN XY: 727214

African (AFR) AF: 0.0891 AC: 2981 AN: 33474

American (AMR) AF: 0.00575 AC: 257 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.000442 AC: 492 AN: 1111974

Other (OTH) AF: 0.00624 AC: 377 AN: 60394

GnomAD4 genome AF: 0.0267 AC: 4061 AN: 152276 Hom.: 182 Cov.: 32 AF XY: 0.0253 AC XY: 1887 AN XY: 74460

African (AFR) AF: 0.0916 AC: 3804 AN: 41548

American (AMR) AF: 0.0111 AC: 170 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68018

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.00869 Hom.: 178

Bravo AF: 0.0302

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0946 AC: 417

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00906 AC: 1100

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	RAB18-related disorder (1)
-	-	1	Warburg micro syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.048
Sift	Benign	0.42	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.42
MPC		0.43
ClinPred		0.0068	T
GERP RS		4.3
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.34
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11015859; hg19: chr10-27826951;