chr17-44075817-A-G

Position:

• chr17-44075817-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000269097.9(G6PC3):​c.815A>G​(p.Gln272Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,611,722 control chromosomes in the GnomAD database, including 77 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q272Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (40 hom.)
• Consequence: G6PC3 ENST00000269097.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024951696).
• BP6: Variant 17-44075817-A-G is Benign according to our data. Variant chr17-44075817-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 323470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44075817-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1864/152304) while in subpopulation AFR AF= 0.0428 (1778/41550). AF 95% confidence interval is 0.0411. There are 37 homozygotes in gnomad4. There are 862 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC3	NM_138387.4	c.815A>G	p.Gln272Arg	missense_variant	6/6	ENST00000269097.9	NP_612396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC3	ENST00000269097.9	c.815A>G	p.Gln272Arg	missense_variant	6/6	1	NM_138387.4	ENSP00000269097	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1865 AN: 152186 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00334 AC: 833 AN: 249548 Hom.: 17 AF XY: 0.00253 AC XY: 342 AN XY: 135100

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00129 AC: 1884 AN: 1459418 Hom.: 40 Cov.: 33 AF XY: 0.00111 AC XY: 809 AN XY: 726168

Gnomad4 AFR exome AF: 0.0440

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.0122 AC: 1864 AN: 152304 Hom.: 37 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74480

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00206 Hom.: 6

Bravo AF: 0.0140

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00422 AC: 512

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.83	L;.
MutationTaster	Benign	0.70	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N;.
REVEL	Benign	0.14
Sift	Benign	0.28	T;.
Sift4G	Benign	0.29	T;T
Polyphen		0.18	B;.
Vest4		0.25
MVP		0.60
MPC		0.33
ClinPred		0.0078	T
GERP RS		4.1
Varity_R		0.067
gMVP		0.19

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

Other links and lift over

dbSNP: rs34491309; hg19: chr17-42153185;