X-47089791-A-G

Variant names:

• chrX-47089791-A-G
• rs1428651510
• NM_152869.4:c.362A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_152869.4(RGN):​c.362A>G​(p.Glu121Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,094,117 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: RGN NM_152869.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06

Genes affected

RGN (HGNC:9989): (regucalcin) The protein encoded by this gene is a highly conserved, calcium-binding protein, that is preferentially expressed in the liver and kidney. It may have an important role in calcium homeostasis. Studies in rat indicate that this protein may also play a role in aging, as it shows age-associated down-regulation. This gene is part of a gene cluster on chromosome Xp11.3-Xp11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity RGN_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.3135596).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGN	NM_152869.4	c.362A>G	p.Glu121Gly	missense_variant	Exon 5 of 8	ENST00000397180.6	NP_690608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGN	ENST00000397180.6	c.362A>G	p.Glu121Gly	missense_variant	Exon 5 of 8	5	NM_152869.4	ENSP00000380365.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1094117 Hom.: 0 Cov.: 29 AF XY: 0.00000556 AC XY: 2 AN XY: 359791

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 19

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.362A>G (p.E121G) alteration is located in exon 5 (coding exon 3) of the RGN gene. This alteration results from a A to G substitution at nucleotide position 362, causing the glutamic acid (E) at amino acid position 121 to be replaced by a glycine (G). 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	0.51
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T;.;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.088
Sift	Benign	0.086	T;T;T
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.070	B;B;B
Vest4		0.40
MutPred		0.61		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.50
MPC		0.017
ClinPred		0.80	D
GERP RS		3.0
Varity_R		0.47
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1428651510; hg19: chrX-46949190;