dbSNP rs769655773: RGPD6:p.Gln24Arg (chr2-110576954-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001123363.4(RGPD6):c.71A>G(p.Gln24Arg) variant causes a missense, splice region change. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q24P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 10)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGPD6
NM_001123363.4 missense, splice_region

Scores

Splicing: ADA: 0.1375

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.28

Variant links:

Genes affected

RGPD6 (HGNC:32419): (RANBP2 like and GRIP domain containing 6) 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]

RGPD6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22511178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD6	NM_001123363.4 link	c.71A>G	p.Gln24Arg	missense_variant, splice_region_variant	Exon 1 of 23	ENST00000329516.8	NP_001116835.1	Q99666-1V9HWE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD6	ENST00000329516.8 link	c.71A>G	p.Gln24Arg	missense_variant, splice_region_variant	Exon 1 of 23	1	NM_001123363.4	ENSP00000330842.3		Q99666-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000368

AC:

AN:

271418

Hom.:

Cov.:

AF XY:

0.00000737

AC XY:

AN XY:

135654

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

5622

American (AMR)

AF:

0.00

AC:

AN:

10740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5616

East Asian (EAS)

AF:

0.00

AC:

AN:

2534

South Asian (SAS)

AF:

0.00

AC:

AN:

19880

European-Finnish (FIN)

AF:

0.0000784

AC:

AN:

12758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

204248

Other (OTH)

AF:

0.00

AC:

AN:

9298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0037

.;.;T

Eigen

Benign

-0.056

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.15

.;.;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.79

PhyloP100

4.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0040

D;D;T

Sift4G

Benign

0.091

T;T;T

Vest4

0.15

MutPred

0.20

Gain of MoRF binding (P = 0.0118);Gain of MoRF binding (P = 0.0118);Gain of MoRF binding (P = 0.0118);

MVP

0.34

MPC

1.7

ClinPred

0.22

GERP RS

1.9

PromoterAI

0.057

Neutral

(source)

gMVP

0.018

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.14

dbscSNV1_RF

Benign

0.53

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.42

Position offset: 42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over