X-47081187-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001282848.2(RGN):​c.-117C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,202,693 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 4 hem., cov: 22)
Exomes 𝑓: 0.0000092 ( 0 hom. 4 hem. )

Consequence

RGN
NM_001282848.2 5_prime_UTR_premature_start_codon_gain

Scores

6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0780
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.24032283).
BS2
High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RGNNM_152869.4 linkc.43C>T p.Arg15Trp missense_variant Exon 3 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.43C>T p.Arg15Trp missense_variant Exon 3 of 8 5 NM_152869.4 ENSP00000380365.1 Q15493-1

Frequencies

GnomAD3 genomes
AF:
0.0000359
AC:
4
AN:
111483
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33697
show subpopulations
Gnomad AFR
AF:
0.0000653
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000374
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
183404
Hom.:
0
AF XY:
0.0000147
AC XY:
1
AN XY:
67842
show subpopulations
Gnomad AFR exome
AF:
0.0000760
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000722
Gnomad SAS exome
AF:
0.0000524
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000916
AC:
10
AN:
1091161
Hom.:
0
Cov.:
28
AF XY:
0.0000112
AC XY:
4
AN XY:
356733
show subpopulations
Gnomad4 AFR exome
AF:
0.0000761
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000994
Gnomad4 SAS exome
AF:
0.0000741
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000218
GnomAD4 genome
AF:
0.0000717
AC:
8
AN:
111532
Hom.:
0
Cov.:
22
AF XY:
0.000118
AC XY:
4
AN XY:
33756
show subpopulations
Gnomad4 AFR
AF:
0.000195
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000375
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 20, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.43C>T (p.R15W) alteration is located in exon 3 (coding exon 1) of the RGN gene. This alteration results from a C to T substitution at nucleotide position 43, causing the arginine (R) at amino acid position 15 to be replaced by a tryptophan (W). 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
0.19
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
.;D;D;D
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.78
T;T;.;.
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.24
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.9
M;M;M;M
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-2.9
D;D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.0090
D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D
Polyphen
0.99
D;D;D;D
Vest4
0.27
MutPred
0.52
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP
0.54
MPC
0.017
ClinPred
0.33
T
GERP RS
-0.033
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.27
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs782549710; hg19: chrX-46940586; COSMIC: COSV60275510; COSMIC: COSV60275510; API