Genetic Variant RGPD6:p.Asp7His (chr2-110577006-C-G) – 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.19G>C(p.Asp7His) 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. 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. D7Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 5)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGPD6
NM_001123363.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.03

Publications

0 publications found

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:

Genome browser will be placed here

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=0.18229905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD6	NM_001123363.4 link	c.19G>C	p.Asp7His	missense_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.19G>C	p.Asp7His	missense_variant	Exon 1 of 23	1	NM_001123363.4	ENSP00000330842.3		Q99666-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

25012

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00000824

AC:

AN:

606896

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

295340

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:

9208

American (AMR)

AF:

0.00

AC:

AN:

11262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8424

East Asian (EAS)

AF:

0.000153

AC:

AN:

6528

South Asian (SAS)

AF:

0.00

AC:

AN:

28246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1458

European-Non Finnish (NFE)

AF:

0.00000788

AC:

AN:

507590

Other (OTH)

AF:

0.00

AC:

AN:

20372

⚠️ 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: 0.285

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

25012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

12770

African (AFR)

AF:

0.00

AC:

AN:

5368

American (AMR)

AF:

0.00

AC:

AN:

3542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

808

East Asian (EAS)

AF:

0.00

AC:

AN:

666

South Asian (SAS)

AF:

0.00

AC:

AN:

376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

12512

Other (OTH)

AF:

0.00

AC:

AN:

350

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.066

.;.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.94

.;.;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.62

PhyloP100

3.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.4

N;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Vest4

0.16

MutPred

0.20

Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);

MVP

0.22

MPC

1.9

ClinPred

0.27

GERP RS

1.0

PromoterAI

-0.042

Neutral

(source)

gMVP

0.080

Mutation Taster

=100/0

polymorphism

(source)

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

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2-110577006-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over