Variant chr19-40783788-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016154.5(RAB4B):c.223C>T(p.Arg75Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,255,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RAB4B
NM_016154.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0230

Variant links:

Genes affected

RAB4B (HGNC:9782): (RAB4B, member RAS oncogene family) Predicted to enable G protein activity and GTP binding activity. Involved in glucose import. Located in insulin-responsive compartment; perinuclear region of cytoplasm; and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB4B links:

MIA-RAB4B (HGNC:):

MIA-RAB4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RAB4B	NM_016154.5 linkuse as main transcript	c.223C>T	p.Arg75Trp	missense_variant	4/8	ENST00000357052.8	NP_057238.3
MIA-RAB4B	NR_037775.1 linkuse as main transcript	n.585C>T		non_coding_transcript_exon_variant	6/10
RAB4B-EGLN2	NR_037791.1 linkuse as main transcript	n.380C>T		non_coding_transcript_exon_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB4B	ENST00000357052.8 linkuse as main transcript	c.223C>T	p.Arg75Trp	missense_variant	4/8	1	NM_016154.5	ENSP00000349560	P1	P61018-1
	ENST00000595728.2 linkuse as main transcript	n.992-3897G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000894

AC:

AN:

223810

Hom.:

AF XY:

0.00000830

AC XY:

AN XY:

120428

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.0000384

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1255520

Hom.:

Cov.:

AF XY:

0.00000809

AC XY:

AN XY:

617770

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000121

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000212

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.223C>T (p.R75W) alteration is located in exon 4 (coding exon 4) of the RAB4B gene. This alteration results from a C to T substitution at nucleotide position 223, causing the arginine (R) at amino acid position 75 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Benign

0.011

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.43

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.8

.;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.025

D;D

Polyphen

0.93

P;P

Vest4

0.91

MutPred

0.66

Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);

MVP

0.90

MPC

0.50

ClinPred

0.98

GERP RS

1.1

Varity_R

0.82

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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