chr17-44075340-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_138387.4(G6PC3):c.566G>A(p.Arg189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

G6PC3
NM_138387.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.12

Publications

7 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008648664).

BP6

Variant 17-44075340-G-A is Benign according to our data. Variant chr17-44075340-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262367.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000801 (122/152224) while in subpopulation AMR AF = 0.0017 (26/15304). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC3	NM_138387.4 link	c.566G>A	p.Arg189Gln	missense_variant	Exon 5 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.566G>A	p.Arg189Gln	missense_variant	Exon 5 of 6	1	NM_138387.4	ENSP00000269097.3		Q9BUM1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.000553

AC:

139

AN:

251410

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000366

AC:

535

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

245

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33480

American (AMR)

AF:

0.00139

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000304

AC:

338

AN:

1112010

Other (OTH)

AF:

0.00104

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000801

AC:

122

AN:

152224

Hom.:

Cov.:

AF XY:

0.000914

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41528

American (AMR)

AF:

0.00170

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68000

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000740

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000568

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Uncertain:1Benign:1

Sep 06, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

D;D

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

L;.

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.53

N;.

REVEL

Benign

0.085

Sift

Benign

0.49

T;.

Sift4G

Benign

0.49

T;T

Polyphen

0.019

B;.

Vest4

0.71

MVP

0.44

MPC

0.35

ClinPred

0.0072

GERP RS

3.3

Varity_R

0.097

gMVP

0.18

Mutation Taster

=93/7

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over