17-5377236-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004703.6(RABEP1):​c.2146G>A​(p.Glu716Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RABEP1
NM_004703.6 missense

Scores

11
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.58
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RABEP1NM_004703.6 linkc.2146G>A p.Glu716Lys missense_variant Exon 14 of 18 ENST00000537505.6 NP_004694.2 Q15276-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RABEP1ENST00000537505.6 linkc.2146G>A p.Glu716Lys missense_variant Exon 14 of 18 1 NM_004703.6 ENSP00000445408.2 Q15276-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2146G>A (p.E716K) alteration is located in exon 14 (coding exon 14) of the RABEP1 gene. This alteration results from a G to A substitution at nucleotide position 2146, causing the glutamic acid (E) at amino acid position 716 to be replaced by a lysine (K). 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
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.51
D;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Benign
-0.60
T
MutationAssessor
Pathogenic
2.9
M;M
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.5
N;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.036
D;T
Polyphen
1.0
D;D
Vest4
0.93
MutPred
0.84
Gain of ubiquitination at E716 (P = 0.0117);Gain of ubiquitination at E716 (P = 0.0117);
MVP
0.75
ClinPred
0.96
D
GERP RS
4.9
Varity_R
0.74
gMVP
0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-5280531; API