2-106423209-A-T

Position:

• chr2-106423209-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000409886.4(RGPD3):​c.4758T>A​(p.Ser1586Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1586T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RGPD3 ENST00000409886.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.109448165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGPD3	NM_001144013.2	c.4758T>A	p.Ser1586Arg	missense_variant	20/23	ENST00000409886.4	NP_001137485.1
RGPD3	XM_017004738.2	c.4782T>A	p.Ser1594Arg	missense_variant	21/24		XP_016860227.1
RGPD3	XM_047445567.1	c.4782T>A	p.Ser1594Arg	missense_variant	21/22		XP_047301523.1
RGPD3	XM_017004739.3	c.4782T>A	p.Ser1594Arg	missense_variant	21/22		XP_016860228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGPD3	ENST00000409886.4	c.4758T>A	p.Ser1586Arg	missense_variant	20/23	1	NM_001144013.2	ENSP00000386588.4
RGPD3	ENST00000304514.11	c.4740T>A	p.Ser1580Arg	missense_variant	20/23	2		ENSP00000303659.8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.4758T>A (p.S1586R) alteration is located in exon 20 (coding exon 20) of the RGPD3 gene. This alteration results from a T to A substitution at nucleotide position 4758, causing the serine (S) at amino acid position 1586 to be replaced by an arginine (R). 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	0.25
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.064	.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.021
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.029	D;D
Polyphen		0.013	.;B
Vest4		0.13
MutPred		0.22		.;Loss of phosphorylation at S1586 (P = 0.0167);
MVP		0.048
ClinPred		0.14	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.015

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-107039665;