chr17-5381475-G-A

Variant names:

• chr17-5381475-G-A
• rs1065483
• NM_004703.6:c.2457G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004703.6(RABEP1):​c.2457G>A​(p.Arg819Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,610,816 control chromosomes in the GnomAD database, including 187,492 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (21594 hom., cov: 32)
  • Exomes 𝑓: 0.46 (165898 hom.)
• Consequence: RABEP1 NM_004703.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.461
• Publications: 46 publications found

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]

NUP88 Gene-Disease associations (from GenCC):

• fetal akinesia deformation sequence 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=0.461 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004703.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RABEP1	NM_004703.6	MANE Select	c.2457G>A	p.Arg819Arg	synonymous	Exon 17 of 18	NP_004694.2
	RABEP1	NM_001083585.3		c.2358G>A	p.Arg786Arg	synonymous	Exon 16 of 17	NP_001077054.1	Q15276-2
	RABEP1	NM_001291581.2		c.2328G>A	p.Arg776Arg	synonymous	Exon 16 of 17	NP_001278510.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RABEP1	ENST00000537505.6	TSL:1 MANE Select	c.2457G>A	p.Arg819Arg	synonymous	Exon 17 of 18	ENSP00000445408.2	Q15276-1
	RABEP1	ENST00000341923.10	TSL:1	c.2358G>A	p.Arg786Arg	synonymous	Exon 16 of 17	ENSP00000339569.6	Q15276-2
	NUP88	ENST00000573169.1	TSL:1	n.71+4663C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78234 AN: 151900 Hom.: 21554 Cov.: 32

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.493

GnomAD2 exomes AF: 0.533 AC: 132450 AN: 248518 AF XY: 0.535

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.972

Gnomad FIN exome AF: 0.597

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.493

GnomAD4 exome AF: 0.460 AC: 670737 AN: 1458798 Hom.: 165898 Cov.: 41 AF XY: 0.467 AC XY: 338614 AN XY: 725640

African (AFR) AF: 0.610 AC: 20349 AN: 33386

American (AMR) AF: 0.506 AC: 22513 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 10439 AN: 26044

East Asian (EAS) AF: 0.978 AC: 38747 AN: 39610

South Asian (SAS) AF: 0.722 AC: 62135 AN: 86006

European-Finnish (FIN) AF: 0.578 AC: 30762 AN: 53240

Middle Eastern (MID) AF: 0.516 AC: 2973 AN: 5760

European-Non Finnish (NFE) AF: 0.408 AC: 453237 AN: 1110024

Other (OTH) AF: 0.491 AC: 29582 AN: 60208

GnomAD4 genome AF: 0.515 AC: 78337 AN: 152018 Hom.: 21594 Cov.: 32 AF XY: 0.531 AC XY: 39429 AN XY: 74312

African (AFR) AF: 0.608 AC: 25194 AN: 41460

American (AMR) AF: 0.482 AC: 7372 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1397 AN: 3466

East Asian (EAS) AF: 0.968 AC: 5003 AN: 5170

South Asian (SAS) AF: 0.743 AC: 3582 AN: 4822

European-Finnish (FIN) AF: 0.604 AC: 6380 AN: 10556

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27993 AN: 67948

Other (OTH) AF: 0.498 AC: 1049 AN: 2108

Alfa AF: 0.446 Hom.: 35446

Bravo AF: 0.508

Asia WGS AF: 0.835 AC: 2898 AN: 3478

EpiCase AF: 0.410

EpiControl AF: 0.410

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.5
DANN	Benign	0.78
PhyloP100		0.46
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1065483; hg19: chr17-5284770; COSMIC: COSV52583947; COSMIC: COSV52583947;