Genetic Variant RAB18:c.187-55T>A (chr10-27532452-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021252.5(RAB18):c.187-55T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,276,490 control chromosomes in the GnomAD database, including 3,993 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.023 ( 314 hom., cov: 32)

Exomes 𝑓: 0.028 ( 3679 hom. )

Consequence

RAB18
NM_021252.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.449

Publications

4 publications found

Variant links:

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

RAB18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAB18	NM_021252.5	MANE Select	c.187-55T>A	intron	N/A	NP_067075.1	Q9NP72-1
RAB18	NM_001256410.2		c.274-55T>A	intron	N/A	NP_001243339.1	Q9NP72-2
RAB18	NM_001256411.2		c.187-55T>A	intron	N/A	NP_001243340.1	B7Z4P9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAB18	ENST00000356940.11	TSL:1 MANE Select	c.187-55T>A	intron	N/A	ENSP00000349415.7	Q9NP72-1
RAB18	ENST00000621805.6	TSL:1	c.274-55T>A	intron	N/A	ENSP00000478479.1	Q9NP72-2
RAB18	ENST00000684501.1		c.187-55T>A	intron	N/A	ENSP00000507589.1	B7Z4P9

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3535

AN:

152034

Hom.:

317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0336

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.304

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.0318

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00306

Gnomad OTH

AF:

0.0225

GnomAD4 exome

AF:

0.0276

AC:

31025

AN:

1124338

Hom.:

3679

AF XY:

0.0302

AC XY:

17375

AN XY:

574978

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

26272

American (AMR)

AF:

0.0502

AC:

2178

AN:

43420

Ashkenazi Jewish (ASJ)

AF:

0.0157

AC:

375

AN:

23860

East Asian (EAS)

AF:

0.378

AC:

14244

AN:

37672

South Asian (SAS)

AF:

0.116

AC:

9047

AN:

77806

European-Finnish (FIN)

AF:

0.0316

AC:

1580

AN:

50002

Middle Eastern (MID)

AF:

0.0203

AC:

AN:

3686

European-Non Finnish (NFE)

AF:

0.00242

AC:

1965

AN:

812676

Other (OTH)

AF:

0.0310

AC:

1517

AN:

48944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1160

2320

3479

4639

5799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0232

AC:

3530

AN:

152152

Hom.:

314

Cov.:

AF XY:

0.0283

AC XY:

2108

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41554

American (AMR)

AF:

0.0338

AC:

517

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3468

East Asian (EAS)

AF:

0.304

AC:

1570

AN:

5172

South Asian (SAS)

AF:

0.141

AC:

681

AN:

4826

European-Finnish (FIN)

AF:

0.0318

AC:

337

AN:

10596

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00306

AC:

208

AN:

67936

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

152

305

457

610

762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.195

AC:

673

AN:

3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

-0.45

PromoterAI

0.0096

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over