rs34406052

Positions:

chr17-44075421-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138387.4(G6PC3):c.647C>T(p.Thr216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,614,152 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. T216T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 35 hom. )

Consequence

G6PC3
NM_138387.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.347

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045161545).

BP6

Variant 17-44075421-C-T is Benign according to our data. Variant chr17-44075421-C-T is described in ClinVar as [Benign]. Clinvar id is 323467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44075421-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1996/152276) while in subpopulation AFR AF= 0.045 (1871/41556). AF 95% confidence interval is 0.0433. There are 40 homozygotes in gnomad4. There are 972 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC3	NM_138387.4 linkuse as main transcript	c.647C>T	p.Thr216Ile	missense_variant	5/6	ENST00000269097.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC3	ENST00000269097.9 linkuse as main transcript	c.647C>T	p.Thr216Ile	missense_variant	5/6	1	NM_138387.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1989

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0450

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00320

AC:

805

AN:

251492

Hom.:

AF XY:

0.00232

AC XY:

316

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00159

AC:

2329

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1040

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0484

Gnomad4 AMR exome

AF:

0.00268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000338

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.0131

AC:

1996

AN:

152276

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

972

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0450

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00286

Hom.:

Bravo

AF:

0.0154

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0427

AC:

188

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00376

AC:

456

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.71

N;.

MutationTaster

Benign

0.87

PrimateAI

Uncertain

0.55

PROVEAN

Benign

1.1

N;.

REVEL

Benign

0.11

Sift

Benign

0.69

T;.

Sift4G

Benign

0.16

T;T

Polyphen

0.0

B;.

Vest4

0.23

MVP

0.36

MPC

0.32

ClinPred

0.012

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.43

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