Genetic Variant RGPD8:p.Gly1670Cys (chr2-112380877-C-A) – 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.5008G>T(p.Gly1670Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 18)

Exomes 𝑓: 0.0000024 ( 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: 0.709

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=0.17320222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD8	NM_001164463.1 link	c.5008G>T	p.Gly1670Cys	missense_variant	Exon 21 of 23	ENST00000302558.8	NP_001157935.1	O14715
RGPD8	XM_024453101.2 link	c.4930G>T	p.Gly1644Cys	missense_variant	Exon 21 of 23		XP_024308869.1
RGPD8	XM_047445676.1 link	c.4153G>T	p.Gly1385Cys	missense_variant	Exon 16 of 18		XP_047301632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD8	ENST00000302558.8 link	c.5008G>T	p.Gly1670Cys	missense_variant	Exon 21 of 23	1	NM_001164463.1	ENSP00000306637.3		O14715
RGPD8	ENST00000409750.5 link	c.4588G>T	p.Gly1530Cys	missense_variant	Exon 20 of 22	1		ENSP00000386511.1		J3KQ37

Frequencies

GnomAD3 genomes

AF:

0.0000149

AC:

AN:

134306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000526

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000241

AC:

AN:

1242888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

621252

show subpopulations

Gnomad4 AFR exome

AF:

0.0000323

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000137

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000189

GnomAD4 genome

AF:

0.0000149

AC:

AN:

134306

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

64398

show subpopulations

Gnomad4 AFR

AF:

0.0000526

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:

0.00

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

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5008G>T (p.G1670C) alteration is located in exon 21 (coding exon 21) of the RGPD8 gene. This alteration results from a G to T substitution at nucleotide position 5008, causing the glycine (G) at amino acid position 1670 to be replaced by a cysteine (C). 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

0.12

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.15

MutPred

0.28

Loss of MoRF binding (P = 0.0837);.;

MVP

0.16

ClinPred

0.78

GERP RS

0.72

Varity_R

0.38

gMVP

0.047

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