4-13369905-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_004249.4(RAB28):c.634A>G(p.Thr212Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RAB28
NM_004249.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0260

Variant links:

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]

RAB28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a chain Ras-related protein Rab-28 (size 216) in uniprot entity RAB28_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004249.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024894446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB28	NM_004249.4 link	c.634A>G	p.Thr212Ala	missense_variant	Exon 7 of 8	ENST00000288723.9	NP_004240.2	P51157-2
RAB28	NM_001017979.3 link	c.574-1255A>G		intron_variant	Intron 6 of 6	ENST00000330852.10	NP_001017979.1	P51157-1
RAB28	NM_001159601.2 link	c.*32-1255A>G		intron_variant	Intron 7 of 7		NP_001153073.1	P51157-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB28	ENST00000288723.9 link	c.634A>G	p.Thr212Ala	missense_variant	Exon 7 of 8	1	NM_004249.4	ENSP00000288723.4		P51157-2
RAB28	ENST00000330852.10 link	c.574-1255A>G		intron_variant	Intron 6 of 6	1	NM_001017979.3	ENSP00000328551.5		P51157-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250804

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460362

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151284

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73818

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 212 of the RAB28 protein (p.Thr212Ala). This variant is present in population databases (rs749902773, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RAB28-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.73

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.14

M_CAP

Benign

0.013

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.72

REVEL

Benign

0.054

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.087

MutPred

0.12

Gain of loop (P = 0.0435);

MVP

0.56

ClinPred

0.055

GERP RS

-1.8

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

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