Genetic Variant RGN:p.Arg129Trp (chrX-47089814-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_152869.4(RGN):c.385C>T(p.Arg129Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,202,656 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. 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. R129Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 3 hem., cov: 19)

Exomes 𝑓: 0.000033 ( 0 hom. 9 hem. )

Consequence

RGN
NM_152869.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

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]

RGN links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGN	NM_152869.4 link	c.385C>T	p.Arg129Trp	missense_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
RGN	ENST00000397180.6 link	c.385C>T	p.Arg129Trp	missense_variant	Exon 5 of 8	5	NM_152869.4	ENSP00000380365.1		Q15493-1

Frequencies

GnomAD3 genomes

AF:

0.0000373

AC:

AN:

107214

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

29724

show subpopulations

Gnomad AFR

AF:

0.0000341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000399

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000334

AC:

AN:

179458

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

64168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000249

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1095442

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

360988

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.0000572

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000559

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000274

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000373

AC:

AN:

107214

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

29724

show subpopulations

Gnomad4 AFR

AF:

0.0000341

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000399

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000382

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385C>T (p.R129W) alteration is located in exon 5 (coding exon 3) of the RGN gene. This alteration results from a C to T substitution at nucleotide position 385, causing the arginine (R) at amino acid position 129 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

0.26

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;D

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

D;.;.

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

3.1

M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.31

MutPred

0.70

Gain of catalytic residue at L127 (P = 0.0045);Gain of catalytic residue at L127 (P = 0.0045);Gain of catalytic residue at L127 (P = 0.0045);

MVP

0.54

MPC

0.12

ClinPred

0.81

GERP RS

3.5

Varity_R

0.72

gMVP

0.63

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over