Genetic Variant NM_001123363.4:c.71A>C (chr2-110576954-T-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001123363.4(RGPD6):c.71A>C(p.Gln24Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 10)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGPD6
NM_001123363.4 missense, splice_region

Scores

Splicing: ADA: 0.1494

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27837372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD6	NM_001123363.4 link	c.71A>C	p.Gln24Pro	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>C	p.Gln24Pro	missense_variant, splice_region_variant	Exon 1 of 23	1	NM_001123363.4	ENSP00000330842.3		Q99666-1

Frequencies

GnomAD3 genomes

AF:

0.0000150

AC:

AN:

66464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000206

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

GnomAD2 exomes

AF:

0.0000233

AC:

AN:

85908

AF XY:

0.0000206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000792

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000255

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000111

AC:

AN:

271418

Hom.:

Cov.:

AF XY:

0.00000737

AC XY:

AN XY:

135654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

5622

American (AMR)

AF:

0.0000931

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:

0.00

AC:

AN:

12758

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

204248

Other (OTH)

AF:

0.000108

AC:

AN:

9298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000150

AC:

AN:

66464

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

30108

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

16394

American (AMR)

AF:

0.000206

AC:

AN:

4844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2192

East Asian (EAS)

AF:

0.00

AC:

AN:

1994

South Asian (SAS)

AF:

0.00

AC:

AN:

1482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

37172

Other (OTH)

AF:

0.00

AC:

AN:

886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

ExAC

AF:

0.0000179

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.71A>C (p.Q24P) alteration is located in exon 2 (coding exon 1) of the RGPD6 gene. This alteration results from a A to C substitution at nucleotide position 71, causing the glutamine (Q) at amino acid position 24 to be replaced by a proline (P). 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

Uncertain

0.46

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.056

.;.;T

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.19

.;.;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.69

PhyloP100

4.3

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0050

D;D;T

Sift4G

Uncertain

0.045

D;T;D

Vest4

0.30

MutPred

0.20

Gain of glycosylation at Q24 (P = 0.0112);Gain of glycosylation at Q24 (P = 0.0112);Gain of glycosylation at Q24 (P = 0.0112);

MVP

0.40

MPC

1.9

ClinPred

0.14

GERP RS

1.9

PromoterAI

0.14

Neutral

(source)

gMVP

0.20

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.15

dbscSNV1_RF

Benign

0.48

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: 42

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

Publications

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NM_001123363.4:c.71A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over