10-27504350-C-T

Variant names:

• chr10-27504350-C-T
• rs74127323
• NM_021252.5:c.-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021252.5(RAB18):​c.-20C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00088 in 1,568,688 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: RAB18 NM_021252.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.592
• Publications: 1 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

LOC124902399 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-27504350-C-T is Benign according to our data. Variant chr10-27504350-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 299813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00408 (621/152324) while in subpopulation AFR AF = 0.0138 (573/41580). AF 95% confidence interval is 0.0128. There are 3 homozygotes in GnomAd4. There are 287 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.-20C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_067075.1	Q9NP72-1
	RAB18	NM_021252.5	MANE Select	c.-20C>T		5_prime_UTR	Exon 1 of 7	NP_067075.1	Q9NP72-1
	RAB18	NM_001256410.2		c.-20C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001243339.1	Q9NP72-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.-20C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000349415.7	Q9NP72-1
	RAB18	ENST00000621805.6	TSL:1	c.-20C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000478479.1	Q9NP72-2
	RAB18	ENST00000356940.11	TSL:1 MANE Select	c.-20C>T		5_prime_UTR	Exon 1 of 7	ENSP00000349415.7	Q9NP72-1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 620 AN: 152206 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00124 AC: 227 AN: 182456 AF XY: 0.00100

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000651

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.000536 AC: 759 AN: 1416364 Hom.: 1 Cov.: 31 AF XY: 0.000507 AC XY: 355 AN XY: 699992

African (AFR) AF: 0.0157 AC: 515 AN: 32890

American (AMR) AF: 0.000920 AC: 34 AN: 36972

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 38054

South Asian (SAS) AF: 0.000186 AC: 15 AN: 80496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49830

Middle Eastern (MID) AF: 0.00419 AC: 19 AN: 4540

European-Non Finnish (NFE) AF: 0.0000881 AC: 96 AN: 1089556

Other (OTH) AF: 0.00134 AC: 79 AN: 58742

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152324 Hom.: 3 Cov.: 32 AF XY: 0.00385 AC XY: 287 AN XY: 74490

African (AFR) AF: 0.0138 AC: 573 AN: 41580

American (AMR) AF: 0.00209 AC: 32 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00483

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Warburg micro syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		-0.59
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs74127323; hg19: chr10-27793279;