17-5365235-C-A

Position:

chr17-5365235-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004703.6(RABEP1):c.1782C>A(p.His594Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,602,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

RABEP1
NM_004703.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.396

Variant links:

Genes affected

RABEP1 (HGNC:17677): (rabaptin, RAB GTPase binding effector protein 1) Enables protein domain specific binding activity and protein homodimerization activity. Involved in vesicle-mediated transport. Located in endocytic vesicle and endosome. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

RABEP1 links:

(HGNC:):

links:

NUP88 (HGNC:8067): (nucleoporin 88) The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins, a family of 50 to 100 proteins, are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene belongs to the nucleoporin family and is associated with the oncogenic nucleoporin CAN/Nup214 in a dynamic subcomplex. This protein is also overexpressed in a large number of malignant neoplasms and precancerous dysplasias. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

NUP88 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RABEP1	NM_004703.6 linkuse as main transcript	c.1782C>A	p.His594Gln	missense_variant	11/18	ENST00000537505.6	NP_004694.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RABEP1	ENST00000537505.6 linkuse as main transcript	c.1782C>A	p.His594Gln	missense_variant	11/18	1	NM_004703.6	ENSP00000445408	P1	Q15276-1
	ENST00000572792.1 linkuse as main transcript	n.382-790G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000537

AC:

AN:

241908

Hom.:

AF XY:

0.0000379

AC XY:

AN XY:

131862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000948

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:

0.0000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

237

AN:

1450142

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

107

AN XY:

721978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000609

Gnomad4 AMR exome

AF:

0.0000944

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.000181

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.0000497

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

Apr 18, 2023

The c.1782C>A (p.H594Q) alteration is located in exon 11 (coding exon 11) of the RABEP1 gene. This alteration results from a C to A substitution at nucleotide position 1782, causing the histidine (H) at amino acid position 594 to be replaced by a glutamine (Q). 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

0.074

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.045

DANN

Benign

0.82

DEOGEN2

Benign

0.069

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.41

.;N

REVEL

Benign

0.021

Sift

Benign

0.61

.;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;B

Vest4

0.14

MutPred

0.35

Loss of catalytic residue at H594 (P = 0.1599);Loss of catalytic residue at H594 (P = 0.1599);

MVP

0.26

ClinPred

0.029

GERP RS

-8.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.054

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