Genetic Variant RGN:p.Asn103Ser (chrX-47084562-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_152869.4(RGN):c.308A>G(p.Asn103Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000692 in 1,197,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 279 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., 10 hem., cov: 24)

Exomes 𝑓: 0.00073 ( 0 hom. 269 hem. )

Consequence

RGN
NM_152869.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity RGN_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

BS2

High Hemizygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGN	NM_152869.4 link	c.308A>G	p.Asn103Ser	missense_variant	Exon 4 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.308A>G	p.Asn103Ser	missense_variant	Exon 4 of 8	5	NM_152869.4	ENSP00000380365.1		Q15493-1

Frequencies

GnomAD3 genomes

AF:

0.000285

AC:

AN:

112405

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

AN XY:

34553

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000526

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000324

AC:

AN:

157180

Hom.:

AF XY:

0.000459

AC XY:

AN XY:

47890

show subpopulations

Gnomad AFR exome

AF:

0.0000890

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000697

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000734

AC:

797

AN:

1085379

Hom.:

Cov.:

AF XY:

0.000761

AC XY:

269

AN XY:

353657

show subpopulations

Gnomad4 AFR exome

AF:

0.0000765

Gnomad4 AMR exome

AF:

0.0000891

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000192

Gnomad4 FIN exome

AF:

0.0000251

Gnomad4 NFE exome

AF:

0.000926

Gnomad4 OTH exome

AF:

0.000372

GnomAD4 genome

AF:

0.000285

AC:

AN:

112405

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

AN XY:

34553

show subpopulations

Gnomad4 AFR

AF:

0.000129

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000526

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000542

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000290

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.308A>G (p.N103S) alteration is located in exon 4 (coding exon 2) of the RGN gene. This alteration results from a A to G substitution at nucleotide position 308, causing the asparagine (N) at amino acid position 103 to be replaced by a serine (S). 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

0.73

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;D;D;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;.

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

4.0

H;H;H;H

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.90

MVP

0.54

MPC

0.13

ClinPred

0.64

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.79

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.

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