Genetic Variant NM_001144013.2:c.4915C>A (chr2-106423052-G-T) – 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_001144013.2(RGPD3):c.4915C>A(p.Pro1639Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 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: 28)

Exomes 𝑓: 0.000057 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGPD3
NM_001144013.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03

Publications

0 publications found

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:

ENSG00000291125 (HGNC:):

ENSG00000291125 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=0.12953103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD3	NM_001144013.2 link	c.4915C>A	p.Pro1639Thr	missense_variant	Exon 20 of 23	ENST00000409886.4	NP_001137485.1	A6NKT7
RGPD3	XM_017004738.2 link	c.4939C>A	p.Pro1647Thr	missense_variant	Exon 21 of 24		XP_016860227.1
RGPD3	XM_047445567.1 link	c.4939C>A	p.Pro1647Thr	missense_variant	Exon 21 of 22		XP_047301523.1
RGPD3	XM_017004739.3 link	c.4939C>A	p.Pro1647Thr	missense_variant	Exon 21 of 22		XP_016860228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD3	ENST00000409886.4 link	c.4915C>A	p.Pro1639Thr	missense_variant	Exon 20 of 23	1	NM_001144013.2	ENSP00000386588.4		A6NKT7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000401

AC:

AN:

174520

AF XY:

0.0000414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000691

Gnomad OTH exome

AF:

0.000234

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000573

AC:

AN:

1431556

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

712374

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:

32022

American (AMR)

AF:

0.00

AC:

AN:

40724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25242

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

82086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.0000709

AC:

AN:

1099944

Other (OTH)

AF:

0.0000677

AC:

AN:

59076

⚠️ 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: 0.336

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: AS_VQSR

AF:

0.0000263

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74176

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:

41328

American (AMR)

AF:

0.0000656

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.004414), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000350

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4915C>A (p.P1639T) alteration is located in exon 20 (coding exon 20) of the RGPD3 gene. This alteration results from a C to A substitution at nucleotide position 4915, causing the proline (P) at amino acid position 1639 to be replaced by a threonine (T). 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

0.079

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.044

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.4

.;N

REVEL

Benign

0.057

Sift

Benign

0.087

.;T

Sift4G

Benign

0.23

T;T

Polyphen

0.79

.;P

Vest4

0.22

MutPred

0.22

.;Loss of loop (P = 0.0073);

MVP

0.088

ClinPred

0.077

GERP RS

1.3

Varity_R

0.16

gMVP

0.034

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_001144013.2:c.4915C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over