Genetic Variant RAB4B:p.Ser76Asn (chr19-40783792-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016154.5(RAB4B):c.227G>A(p.Ser76Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAB4B
NM_016154.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Publications

0 publications found

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:

RAB4B-EGLN2 (HGNC:44465): (RAB4B-EGLN2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RAB4B (RAB4B, member RAS oncogene family) and EGLN2 (egl nine homolog 2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

RAB4B-EGLN2 links:

MIA-RAB4B (HGNC:48352): (MIA-RAB4B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MIA (melanoma inhibitory activity) and RAB4B (RAB4B, member RAS oncogene family) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

MIA-RAB4B links:

ENSG00000282951 (HGNC:):

ENSG00000282951 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016154.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAB4B	NM_016154.5	MANE Select	c.227G>A	p.Ser76Asn	missense	Exon 4 of 8	NP_057238.3
MIA-RAB4B	NR_037775.1		n.589G>A		non_coding_transcript_exon	Exon 6 of 10
RAB4B-EGLN2	NR_037791.1		n.384G>A		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB4B	ENST00000357052.8	TSL:1 MANE Select	c.227G>A	p.Ser76Asn	missense	Exon 4 of 8	ENSP00000349560.2	P61018-1
RAB4B	ENST00000378307.9	TSL:1	n.227G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000367557.4	F6SQB9
RAB4B-EGLN2	ENST00000594136.2	TSL:2	n.227G>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000469872.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1266978

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

623844

African (AFR)

AF:

0.00

AC:

AN:

27972

American (AMR)

AF:

0.00

AC:

AN:

36254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18260

East Asian (EAS)

AF:

0.00

AC:

AN:

26100

South Asian (SAS)

AF:

0.00

AC:

AN:

80420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3510

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

989568

Other (OTH)

AF:

0.00

AC:

AN:

48022

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.5

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.55

Sift

Benign

0.084

Sift4G

Uncertain

0.043

Polyphen

0.029

Vest4

0.81

MutPred

0.75

Loss of phosphorylation at S76 (P = 0.0594)

MVP

0.68

MPC

0.32

ClinPred

0.95

GERP RS

4.8

Varity_R

0.48

gMVP

0.64

Mutation Taster

=21/79

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over