Genetic Variant RGPD8:p.Pro1598Arg (chr2-112388152-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164463.1(RGPD8):c.4793C>G(p.Pro1598Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGPD8
NM_001164463.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.750

Variant links:

Genes affected

RGPD8 (HGNC:9849): (RANBP2 like and GRIP domain containing 8) Predicted to contribute to GTPase activator activity. Predicted to be involved in NLS-bearing protein import into nucleus. Predicted to be part of nuclear pore. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RGPD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11462444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD8	NM_001164463.1 link	c.4793C>G	p.Pro1598Arg	missense_variant	Exon 20 of 23	ENST00000302558.8	NP_001157935.1	O14715

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD8	ENST00000302558.8 link	c.4793C>G	p.Pro1598Arg	missense_variant	Exon 20 of 23	1	NM_001164463.1	ENSP00000306637.3		O14715
RGPD8	ENST00000409750.5 link	c.4373C>G	p.Pro1458Arg	missense_variant	Exon 19 of 22	1		ENSP00000386511.1		J3KQ37

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

117948

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000457

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

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000440

AC:

AN:

1136288

Hom.:

Cov.:

AF XY:

0.00000351

AC XY:

AN XY:

569726

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000696

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:

0.00

Gnomad4 OTH exome

AF:

0.0000610

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000424

AC:

AN:

118036

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

55918

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000456

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4793C>G (p.P1598R) alteration is located in exon 20 (coding exon 20) of the RGPD8 gene. This alteration results from a C to G substitution at nucleotide position 4793, causing the proline (P) at amino acid position 1598 to be replaced by an arginine (R). 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

0.086

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.031

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.83

T;T

Polyphen

1.0

D;.

Vest4

0.14

MutPred

0.31

Loss of sheet (P = 0.0228);.;

MVP

0.14

ClinPred

0.67

GERP RS

1.3

Varity_R

0.20

gMVP

0.015

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