Genetic Variant RAB18:c.68+264C>T (chr10-27504701-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_021252.5(RAB18):c.68+264C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 696,440 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0038 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 38 hom. )

Consequence

RAB18
NM_021252.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.719

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 links:

LOC124902399 (HGNC:):

LOC124902399 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 10-27504701-C-T is Benign according to our data. Variant chr10-27504701-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1198375.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0038 (579/152304) while in subpopulation SAS AF= 0.013 (63/4830). AF 95% confidence interval is 0.0105. There are 7 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB18	NM_021252.5 link	c.68+264C>T		intron_variant	Intron 1 of 6	ENST00000356940.11	NP_067075.1	Q9NP72-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB18	ENST00000356940.11 link	c.68+264C>T		intron_variant	Intron 1 of 6	1	NM_021252.5	ENSP00000349415.7		Q9NP72-1

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

579

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0232

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00284

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00609

AC:

1072

AN:

175972

Hom.:

AF XY:

0.00690

AC XY:

665

AN XY:

96418

show subpopulations

Gnomad AFR exome

AF:

0.000441

Gnomad AMR exome

AF:

0.000931

Gnomad ASJ exome

AF:

0.000342

Gnomad EAS exome

AF:

0.0000756

Gnomad SAS exome

AF:

0.0166

Gnomad FIN exome

AF:

0.0230

Gnomad NFE exome

AF:

0.00303

Gnomad OTH exome

AF:

0.00399

GnomAD4 exome

AF:

0.00617

AC:

3357

AN:

544136

Hom.:

Cov.:

AF XY:

0.00662

AC XY:

1962

AN XY:

296376

show subpopulations

Gnomad4 AFR exome

AF:

0.000640

Gnomad4 AMR exome

AF:

0.00120

Gnomad4 ASJ exome

AF:

0.000157

Gnomad4 EAS exome

AF:

0.000234

Gnomad4 SAS exome

AF:

0.0166

Gnomad4 FIN exome

AF:

0.0247

Gnomad4 NFE exome

AF:

0.00326

Gnomad4 OTH exome

AF:

0.00455

GnomAD4 genome

AF:

0.00380

AC:

579

AN:

152304

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0130

Gnomad4 FIN

AF:

0.0232

Gnomad4 NFE

AF:

0.00284

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00210

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 27, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.8

DANN

Benign

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over