17-5373449-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004703.6(RABEP1):c.2020A>G(p.Thr674Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 1,602,880 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 0.00028 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: RABEP1 NM_004703.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.398

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]

ACMG classification

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=0.012929261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABEP1	NM_004703.6	c.2020A>G	p.Thr674Ala	missense_variant	13/18	ENST00000537505.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABEP1	ENST00000537505.6	c.2020A>G	p.Thr674Ala	missense_variant	13/18	1	NM_004703.6	P1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 42 AN: 151656 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000896

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000711 AC: 17 AN: 238994 Hom.: 0 AF XY: 0.0000540 AC XY: 7 AN XY: 129578

Gnomad AFR exome AF: 0.000850

Gnomad AMR exome AF: 0.000127

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000386 AC: 56 AN: 1451224 Hom.: 0 Cov.: 31 AF XY: 0.0000374 AC XY: 27 AN XY: 721480

Gnomad4 AFR exome AF: 0.00112

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000277 AC: 42 AN: 151656 Hom.: 0 Cov.: 29 AF XY: 0.000257 AC XY: 19 AN XY: 74002

Gnomad4 AFR AF: 0.000896

Gnomad4 AMR AF: 0.000329

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000295

ESP6500AA AF: 0.00131 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.2020A>G (p.T674A) alteration is located in exon 13 (coding exon 13) of the RABEP1 gene. This alteration results from a A to G substitution at nucleotide position 2020, causing the threonine (T) at amino acid position 674 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.1
Dann	Benign	0.83
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.057	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.76	N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
REVEL	Benign	0.075
Sift4G	Benign	0.76	T;T
Polyphen		0.0	B;B
Vest4		0.058
MVP		0.28
ClinPred		0.0046	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200444793; hg19: chr17-5276744;