Variant 3-19950914-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004162.5(RAB5A):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,611,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

RAB5A
NM_004162.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96

Variant links:

Genes affected

RAB5A (HGNC:9783): (RAB5A, member RAS oncogene family) Enables GDP binding activity; GTP binding activity; and GTPase activity. Involved in several processes, including amyloid-beta clearance by transcytosis; early endosome to late endosome transport; and regulation of exocytosis. Located in several cellular components, including cytoplasmic side of early endosome membrane; nucleoplasm; and terminal bouton. [provided by Alliance of Genome Resources, Apr 2022]

RAB5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26837736).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB5A	NM_004162.5 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	2/6	ENST00000273047.9	NP_004153.2
RAB5A	NM_001292048.2 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	2/6		NP_001278977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB5A	ENST00000273047.9 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	2/6	1	NM_004162.5	ENSP00000273047	P1	P20339-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000758

AC:

AN:

250820

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135590

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:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000182

AC:

265

AN:

1459000

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

725794

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

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

Oct 14, 2021

The c.16G>A (p.A6T) alteration is located in exon 2 (coding exon 1) of the RAB5A gene. This alteration results from a G to A substitution at nucleotide position 16, causing the alanine (A) at amino acid position 6 to be replaced by a threonine (T). 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

Benign

0.078

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;.;.

Eigen

Benign

0.078

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

T;.;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.38

N;.;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.46

N;D;N

REVEL

Benign

0.19

Sift

Benign

0.17

T;.;T

Sift4G

Benign

0.22

T;.;T

Polyphen

0.0060

B;.;.

Vest4

0.64

MVP

0.72

MPC

0.45

ClinPred

0.16

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.47

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