Genetic Variant NM_002868.4:c.29A>T (chr12-55986989-A-T) – 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_002868.4(RAB5B):c.29A>T(p.Asn10Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000876 in 1,484,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N10S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RAB5B
NM_002868.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.21

Publications

0 publications found

Variant links:

Genes affected

RAB5B (HGNC:9784): (RAB5B, member RAS oncogene family) Enables GDP binding activity; GTP-dependent protein binding activity; and GTPase activity. Involved in antigen processing and presentation and plasma membrane to endosome transport. Located in endosome and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB5B 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB5B	NM_002868.4 link	c.29A>T	p.Asn10Ile	missense_variant	Exon 2 of 6	ENST00000360299.10	NP_002859.1	P61020-1A0A024RB09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5B	ENST00000360299.10 link	c.29A>T	p.Asn10Ile	missense_variant	Exon 2 of 6	1	NM_002868.4	ENSP00000353444.5		P61020-1

Frequencies

GnomAD3 genomes

AF:

0.0000141

AC:

AN:

141506

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000262

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251432

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000819

AC:

AN:

1343338

Hom.:

Cov.:

AF XY:

0.00000600

AC XY:

AN XY:

667134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30086

American (AMR)

AF:

0.00

AC:

AN:

40992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21786

East Asian (EAS)

AF:

0.00

AC:

AN:

29010

South Asian (SAS)

AF:

0.00

AC:

AN:

85162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5078

European-Non Finnish (NFE)

AF:

0.0000106

AC:

AN:

1036038

Other (OTH)

AF:

0.00

AC:

AN:

52198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000141

AC:

AN:

141506

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68322

show subpopulations

African (AFR)

AF:

0.0000262

AC:

AN:

38228

American (AMR)

AF:

0.00

AC:

AN:

13828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.00

AC:

AN:

4250

South Asian (SAS)

AF:

0.00

AC:

AN:

4084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65802

Other (OTH)

AF:

0.00

AC:

AN:

1976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T;T;T;T;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.61

D;D;D;D;D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.4

L;L;.;.;.;L;.

PhyloP100

9.2

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0020

D;D;D;D;D;D;.

Sift4G

Benign

0.17

T;T;T;D;T;T;T

Polyphen

0.010

B;B;.;.;.;.;.

Vest4

0.73

MVP

0.81

MPC

1.8

ClinPred

0.91

GERP RS

4.9

PromoterAI

0.11

Neutral

(source)

Varity_R

0.66

gMVP

0.58

Mutation Taster

=44/56

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

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NM_002868.4:c.29A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over