X-47089778-A-G

Variant names:

• chrX-47089778-A-G
• rs782683329
• NM_152869.4:c.349A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152869.4(RGN):​c.349A>G​(p.Thr117Ala) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: RGN NM_152869.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGN	NM_152869.4	c.349A>G	p.Thr117Ala	missense_variant, splice_region_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.349A>G	p.Thr117Ala	missense_variant, splice_region_variant	Exon 5 of 8	5	NM_152869.4	ENSP00000380365.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD3 exomes AF: 0.00000569 AC: 1 AN: 175863 Hom.: 0 AF XY: 0.0000164 AC XY: 1 AN XY: 60815

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000747

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 19

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349A>G (p.T117A) 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 349, causing the threonine (T) at amino acid position 117 to be replaced by an alanine (A). 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	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;.;.
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.4	M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.099	T;T;T
Polyphen		0.72	P;P;P
Vest4		0.91
MutPred		0.72		Loss of glycosylation at T117 (P = 0.0382);Loss of glycosylation at T117 (P = 0.0382);Loss of glycosylation at T117 (P = 0.0382);
MVP		0.52
MPC		0.053
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.79
gMVP		0.74

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: rs782683329; hg19: chrX-46949177;