chr4-13369923-TTTCTTCTTCCGGG-T

Position:

• chr4-13369923-TTTCTTCTTCCGGG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004249.4(RAB28):​c.603_615delCCCGGAAGAAGAA​(p.Tyr201fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB28 NM_004249.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.20

Genes affected

RAB28 (HGNC:9768): (RAB28, member RAS oncogene family) This gene encodes a member of the Rab subfamily of Ras-related small GTPases. The encoded protein may be involved in regulating intracellular trafficking. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 9 and X. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0905 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-13369923-TTTCTTCTTCCGGG-T is Pathogenic according to our data. Variant chr4-13369923-TTTCTTCTTCCGGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 2093933.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB28	NM_004249.4	c.603_615delCCCGGAAGAAGAA	p.Tyr201fs	frameshift_variant	7/8	ENST00000288723.9	NP_004240.2
RAB28	NM_001017979.3	c.574-1286_574-1274delCCCGGAAGAAGAA		intron_variant		ENST00000330852.10	NP_001017979.1
RAB28	NM_001159601.2	c.*32-1286_*32-1274delCCCGGAAGAAGAA		intron_variant			NP_001153073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB28	ENST00000288723.9	c.603_615delCCCGGAAGAAGAA	p.Tyr201fs	frameshift_variant	7/8	1	NM_004249.4	ENSP00000288723.4
RAB28	ENST00000330852.10	c.574-1286_574-1274delCCCGGAAGAAGAA		intron_variant		1	NM_001017979.3	ENSP00000328551.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Tyr201*) in the RAB28 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB28 are known to be pathogenic (PMID: 23746546, 25356532, 27529348). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAB28-related conditions. ClinVar contains an entry for this variant (Variation ID: 2093933). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-13371547;