Genetic Variant RGPD3:p.Gly1671Ser (chr2-106415903-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001144013.2(RGPD3):c.5011G>A(p.Gly1671Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,611,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RGPD3
NM_001144013.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.662

Variant links:

Genes affected

RGPD3 (HGNC:32416): (RANBP2 like and GRIP domain containing 3) This gene is located in a cluster of Ran-binding protein related genes on chromosome 2 which arose through duplication in primates. The encoded protein contains an N-terminal TPR (tetratricopeptide repeat) domain, two Ran-binding domains, and a C-terminal GRIP domain (golgin-97, RanBP2alpha, Imh1p and p230/golgin-245) domain. [provided by RefSeq, Sep 2011]

RGPD3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07094121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD3	NM_001144013.2 link	c.5011G>A	p.Gly1671Ser	missense_variant	Exon 21 of 23	ENST00000409886.4	NP_001137485.1	A6NKT7
RGPD3	XM_017004738.2 link	c.5035G>A	p.Gly1679Ser	missense_variant	Exon 22 of 24		XP_016860227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD3	ENST00000409886.4 link	c.5011G>A	p.Gly1671Ser	missense_variant	Exon 21 of 23	1	NM_001144013.2	ENSP00000386588.4		A6NKT7
RGPD3	ENST00000304514.11 link	c.4993G>A	p.Gly1665Ser	missense_variant	Exon 21 of 23	2		ENSP00000303659.8		J3KNE0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

249640

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1459696

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726156

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151974

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5011G>A (p.G1671S) alteration is located in exon 21 (coding exon 21) of the RGPD3 gene. This alteration results from a G to A substitution at nucleotide position 5011, causing the glycine (G) at amino acid position 1671 to be replaced by a serine (S). 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

0.088

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0035

.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.071

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

.;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.17

.;N

REVEL

Benign

0.026

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.094

T;T

Polyphen

0.22

.;B

Vest4

0.18

MutPred

0.29

.;Gain of disorder (P = 0.0284);

MVP

0.030

ClinPred

0.12

GERP RS

0.70

Varity_R

0.15

gMVP

0.035

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