NM_001144013.2:c.5255C>T

Variant names:

• chr2-106413095-G-A
• rs747052856
• NM_001144013.2:c.5255C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001144013.2(RGPD3):​c.5255C>T​(p.Ala1752Val) variant causes a missense change. The variant allele was found at a frequency of 0.000132 in 1,610,412 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (4 hom.)
• Consequence: RGPD3 NM_001144013.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 0 publications found

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]

ENSG00000291125 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07184246).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD3	NM_001144013.2	c.5255C>T	p.Ala1752Val	missense_variant	Exon 22 of 23	ENST00000409886.4	NP_001137485.1
RGPD3	XM_017004738.2	c.5279C>T	p.Ala1760Val	missense_variant	Exon 23 of 24		XP_016860227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD3	ENST00000409886.4	c.5255C>T	p.Ala1752Val	missense_variant	Exon 22 of 23	1	NM_001144013.2	ENSP00000386588.4

Frequencies

GnomAD3 genomes AF: 0.000212 AC: 32 AN: 151010 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000651

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 249164 AF XY: 0.000170

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1459292 Hom.: 4 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 725936

African (AFR) AF: 0.000269 AC: 9 AN: 33402

American (AMR) AF: 0.0000671 AC: 3 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.000430 AC: 37 AN: 86048

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00146 AC: 6 AN: 4114

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111710

Other (OTH) AF: 0.000133 AC: 8 AN: 60170

GnomAD4 genome AF: 0.000212 AC: 32 AN: 151120 Hom.: 1 Cov.: 28 AF XY: 0.000244 AC XY: 18 AN XY: 73696

African (AFR) AF: 0.000315 AC: 13 AN: 41242

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5088

South Asian (SAS) AF: 0.000652 AC: 3 AN: 4604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5255C>T (p.A1752V) alteration is located in exon 22 (coding exon 22) of the RGPD3 gene. This alteration results from a C to T substitution at nucleotide position 5255, causing the alanine (A) at amino acid position 1752 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0029	.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	.;L
PhyloP100		4.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.17	.;N
REVEL	Benign	0.099
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.13	T;D
Polyphen		0.0030	.;B
Vest4		0.30
MVP		0.030
ClinPred		0.11	T
GERP RS		0.17
Varity_R		0.12
gMVP		0.094
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs747052856; hg19: chr2-107029551; COSMIC: COSV100450685;