X-47089778-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_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

Scores

4
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.26
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
RGNNM_152869.4 linkc.349A>G p.Thr117Ala missense_variant, splice_region_variant Exon 5 of 8 ENST00000397180.6 NP_690608.1 Q15493-1V9HWF8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RGNENST00000397180.6 linkc.349A>G p.Thr117Ala missense_variant, splice_region_variant Exon 5 of 8 5 NM_152869.4 ENSP00000380365.1 Q15493-1

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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782683329; hg19: chrX-46949177; API