Variant 4-13369953-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004249.4(RAB28):c.586G>A(p.Ala196Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,611,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

RAB28
NM_004249.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2686007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB28	NM_004249.4 linkuse as main transcript	c.586G>A	p.Ala196Thr	missense_variant	7/8	ENST00000288723.9	NP_004240.2	P51157-2
RAB28	NM_001017979.3 linkuse as main transcript	c.574-1303G>A		intron_variant		ENST00000330852.10	NP_001017979.1	P51157-1
RAB28	NM_001159601.2 linkuse as main transcript	c.*32-1303G>A		intron_variant			NP_001153073.1	P51157-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB28	ENST00000288723.9 linkuse as main transcript	c.586G>A	p.Ala196Thr	missense_variant	7/8	1	NM_004249.4	ENSP00000288723.4		P51157-2
RAB28	ENST00000330852.10 linkuse as main transcript	c.574-1303G>A		intron_variant		1	NM_001017979.3	ENSP00000328551.5		P51157-1

Frequencies

GnomAD3 genomes

AF:

0.0000727

AC:

AN:

151272

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00106

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000879

AC:

AN:

250310

Hom.:

AF XY:

0.0000887

AC XY:

AN XY:

135338

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000892

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1459916

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726266

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000776

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000727

AC:

AN:

151272

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73788

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00106

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000524

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2021

This variant has not been reported in the literature in individuals affected with RAB28-related conditions. This variant is present in population databases (rs201945581, ExAC 0.06%). This sequence change replaces alanine with threonine at codon 196 of the RAB28 protein (p.Ala196Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Uncertain

0.045

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Pathogenic

1.0

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.040

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.82

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.47

MutPred

0.30

Gain of methylation at K200 (P = 0.0634);

MVP

0.88

ClinPred

0.24

GERP RS

5.0

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