Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:5

Conservation

PhyloP100: -0.347

Publications

9 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 -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 VariationId is 323467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138387.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
G6PC3	NM_138387.4	MANE Select	c.647C>T	p.Thr216Ile	missense	Exon 5 of 6	NP_612396.1
G6PC3	NM_001384165.1		c.302C>T	p.Thr101Ile	missense	Exon 5 of 6	NP_001371094.1
G6PC3	NM_001384166.1		c.302C>T	p.Thr101Ile	missense	Exon 6 of 7	NP_001371095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
G6PC3	ENST00000269097.9	TSL:1 MANE Select	c.647C>T	p.Thr216Ile	missense	Exon 5 of 6	ENSP00000269097.3
G6PC3	ENST00000588558.6	TSL:1	n.*622C>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000467624.1
G6PC3	ENST00000588558.6	TSL:1	n.*622C>T		3_prime_UTR	Exon 6 of 7	ENSP00000467624.1

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

GnomAD2 exomes

AF:

0.00320

AC:

805

AN:

251492

AF XY:

0.00232

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 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

African (AFR)

AF:

0.0484

AC:

1621

AN:

33476

American (AMR)

AF:

0.00268

AC:

120

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000338

AC:

376

AN:

1111998

Other (OTH)

AF:

0.00278

AC:

168

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

149

297

446

594

743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0131

AC:

1996

AN:

152276

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

972

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0450

AC:

1871

AN:

41556

American (AMR)

AF:

0.00464

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68006

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

102

204

306

408

510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00547

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.20

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.71

PhyloP100

-0.35

PrimateAI

Uncertain

0.55

PROVEAN

Benign

1.1

REVEL

Benign

0.11

Sift

Benign

0.69

Sift4G

Benign

0.16

Polyphen

0.0

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

Mutation Taster

=89/11

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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rs34406052

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over