rs118203968

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_138387.4(G6PC3):c.758G>A(p.Arg253His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

G6PC3
NM_138387.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 6.73

Publications

17 publications found

Variant links:

Genes affected

G6PC3 (HGNC:24861): (glucose-6-phosphatase catalytic subunit 3) This gene encodes the catalytic subunit of glucose-6-phosphatase (G6Pase). G6Pase is located in the endoplasmic reticulum (ER) and catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the last step of the gluconeogenic and glycogenolytic pathways. Mutations in this gene result in autosomal recessive severe congenital neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

G6PC3 Gene-Disease associations (from GenCC):

autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

G6PC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-44075759-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 960968.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 17-44075760-G-A is Pathogenic according to our data. Variant chr17-44075760-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC3	NM_138387.4 link	c.758G>A	p.Arg253His	missense_variant	Exon 6 of 6	ENST00000269097.9	NP_612396.1	Q9BUM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC3	ENST00000269097.9 link	c.758G>A	p.Arg253His	missense_variant	Exon 6 of 6	1	NM_138387.4	ENSP00000269097.3		Q9BUM1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

250074

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460216

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111970

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000188

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 253 of the G6PC3 protein (p.Arg253His). This variant is present in population databases (rs118203968, gnomAD 0.002%). This missense change has been observed in individuals with severe congenital neutropenia (PMID: 19118303, 20717171, 21385794). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1037). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt G6PC3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PC3 function (PMID: 19118303). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

G6PC3: PM3:Very Strong, PM2, PP1, PS3:Supporting -

Aug 14, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on G6PC3 phosphatase activity (Boztug et al., 2009; Lin et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21385794, 23196894, 27051561, 34964150, 20616219, 32051561, 19118303, 25491320, 20717171, 34305938, 25284454, 33259599, 25492228) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

6.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.3

D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.88

Loss of methylation at R253 (P = 0.0185);.;

MVP

0.92

MPC

1.1

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.89

Mutation Taster

=31/69

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over