10-27504701-C-T

Variant names:

• chr10-27504701-C-T
• rs146545118
• NM_021252.5:c.68+264C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.719
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• 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	c.68+264C>T		intron_variant	Intron 1 of 6	ENST00000356940.11	NP_067075.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 579 AN: 152186 Hom.: 7 Cov.: 33

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

GnomAD2 exomes AF: 0.00609 AC: 1072 AN: 175972 AF XY: 0.00690

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 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.: 38 Cov.: 4 AF XY: 0.00662 AC XY: 1962 AN XY: 296376

African (AFR) AF: 0.000640 AC: 10 AN: 15624

American (AMR) AF: 0.00120 AC: 44 AN: 36684

Ashkenazi Jewish (ASJ) AF: 0.000157 AC: 3 AN: 19102

East Asian (EAS) AF: 0.000234 AC: 7 AN: 29974

South Asian (SAS) AF: 0.0166 AC: 1061 AN: 63930

European-Finnish (FIN) AF: 0.0247 AC: 1085 AN: 43890

Middle Eastern (MID) AF: 0.00911 AC: 29 AN: 3184

European-Non Finnish (NFE) AF: 0.00326 AC: 987 AN: 302968

Other (OTH) AF: 0.00455 AC: 131 AN: 28780

GnomAD4 genome AF: 0.00380 AC: 579 AN: 152304 Hom.: 7 Cov.: 33 AF XY: 0.00458 AC XY: 341 AN XY: 74472

African (AFR) AF: 0.000553 AC: 23 AN: 41572

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0130 AC: 63 AN: 4830

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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
PhyloP100		-0.72
PromoterAI		-0.0026	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs146545118; hg19: chr10-27793630;