Variant 18-9522420-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000383432.8(RALBP1):c.964A>G(p.Ile322Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,614,214 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

RALBP1
ENST00000383432.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

RALBP1 (HGNC:9841): (ralA binding protein 1) RALBP1 plays a role in receptor-mediated endocytosis and is a downstream effector of the small GTP-binding protein RAL (see RALA; MIM 179550). Small G proteins, such as RAL, have GDP-bound inactive and GTP-bound active forms, which shift from the inactive to the active state through the action of RALGDS (MIM 601619), which in turn is activated by RAS (see HRAS; MIM 190020) (summary by Feig, 2003 [PubMed 12888294]).[supplied by OMIM, Nov 2010]

RALBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029099524).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALBP1	NM_006788.4 linkuse as main transcript	c.964A>G	p.Ile322Val	missense_variant	4/10	ENST00000383432.8	NP_006779.1	Q15311

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALBP1	ENST00000383432.8 linkuse as main transcript	c.964A>G	p.Ile322Val	missense_variant	4/10	1	NM_006788.4	ENSP00000372924.3		Q15311
RALBP1	ENST00000019317.8 linkuse as main transcript	c.964A>G	p.Ile322Val	missense_variant	4/10	1		ENSP00000019317.4		Q15311

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

250580

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000166

AC:

243

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000112

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

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

Aug 08, 2022

The c.964A>G (p.I322V) alteration is located in exon 4 (coding exon 3) of the RALBP1 gene. This alteration results from a A to G substitution at nucleotide position 964, causing the isoleucine (I) at amino acid position 322 to be replaced by a valine (V). 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

0.065

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.56

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.027

Sift

Benign

0.21

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0070

B;B

Vest4

0.12

MVP

0.093

MPC

0.42

ClinPred

0.011

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.13

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