Genetic Variant RGPD1:p.Val1308Ile (chr2-86986821-G-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_001382344.1(RGPD1):c.3922G>A(p.Val1308Ile) variant causes a missense change. 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 0.00019 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000045 ( 8 hom. )

Failed GnomAD Quality Control

Consequence

RGPD1
NM_001382344.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.36

Variant links:

Genes affected

RGPD1 (HGNC:32414): (RANBP2 like and GRIP domain containing 1) 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]

RGPD1 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=0.20283967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD1	NM_001382344.1 link	c.3922G>A	p.Val1308Ile	missense_variant	Exon 20 of 23	ENST00000641458.2	NP_001369273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RGPD1	ENST00000641458.2 link	c.3922G>A	p.Val1308Ile	missense_variant	Exon 20 of 23		NM_001382344.1	ENSP00000492954.1	A0A286YES2
RGPD1	ENST00000398193.8 link	c.3922G>A	p.Val1308Ile	missense_variant	Exon 20 of 23	1		ENSP00000381253.3	F8VYC4
RGPD1	ENST00000428128.1 link	n.*1841G>A		non_coding_transcript_exon_variant	Exon 7 of 10	1		ENSP00000402729.1	H7C1V8
RGPD1	ENST00000428128.1 link	n.*1841G>A		3_prime_UTR_variant	Exon 7 of 10	1		ENSP00000402729.1	H7C1V8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

68458

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000173

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:

0.0000454

AC:

AN:

1388976

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

695136

show subpopulations

Gnomad4 AFR exome

AF:

0.00184

Gnomad4 AMR exome

AF:

0.0000676

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000757

Gnomad4 OTH exome

AF:

0.000139

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000190

AC:

AN:

68518

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

AN XY:

32106

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.000172

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:

0.000590

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3898G>A (p.V1300I) alteration is located in exon 20 (coding exon 20) of the RGPD1 gene. This alteration results from a G to A substitution at nucleotide position 3898, causing the valine (V) at amino acid position 1300 to be replaced by an isoleucine (I). 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

0.10

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

T;.;T;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;.;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.3

M;.;M;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.69

N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.23

T;T;T;.

Sift4G

Benign

0.14

T;T;T;.

Polyphen

0.96

.;D;.;.

Vest4

0.13

MVP

0.076

ClinPred

0.52

GERP RS

2.4

Varity_R

0.045

gMVP

0.014

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