2-106415974-T-C

Position:

• chr2-106415974-T-C

Variant summary

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

The ENST00000409886.4(RGPD3):​c.4940A>G​(p.Tyr1647Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y1647N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RGPD3 ENST00000409886.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

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=0.091878206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGPD3	NM_001144013.2	c.4940A>G	p.Tyr1647Cys	missense_variant	21/23	ENST00000409886.4	NP_001137485.1
RGPD3	XM_017004738.2	c.4964A>G	p.Tyr1655Cys	missense_variant	22/24		XP_016860227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGPD3	ENST00000409886.4	c.4940A>G	p.Tyr1647Cys	missense_variant	21/23	1	NM_001144013.2	ENSP00000386588.4
RGPD3	ENST00000304514.11	c.4922A>G	p.Tyr1641Cys	missense_variant	21/23	2		ENSP00000303659.8

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459672 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

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

Jan 23, 2024

The c.4940A>G (p.Y1647C) alteration is located in exon 21 (coding exon 21) of the RGPD3 gene. This alteration results from a A to G substitution at nucleotide position 4940, causing the tyrosine (Y) at amino acid position 1647 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.0062	.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.10	.;N
REVEL	Benign	0.086
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.0090	.;B
Vest4		0.22
MutPred		0.35		.;Loss of methylation at K1652 (P = 0.0912);
MVP		0.085
ClinPred		0.18	T
GERP RS		0.70
Varity_R		0.15
gMVP		0.020

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

LitVar

Other links and lift over

dbSNP: rs1676816096; hg19: chr2-107032430;