17-44070981-G-T

Position:

• chr17-44070981-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138387.4(G6PC3):​c.16G>T​(p.Gly6Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,401,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: G6PC3 NM_138387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.182

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22296622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC3	NM_138387.4	c.16G>T	p.Gly6Cys	missense_variant	1/6	ENST00000269097.9	NP_612396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC3	ENST00000269097.9	c.16G>T	p.Gly6Cys	missense_variant	1/6	1	NM_138387.4	ENSP00000269097	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1401566 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000890 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 6 of the G6PC3 protein (p.Gly6Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with G6PC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1060064). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt G6PC3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.22
Sift	Benign	0.040	D;.
Sift4G	Uncertain	0.048	D;D
Polyphen		0.86	P;.
Vest4		0.12
MutPred		0.34		Loss of disorder (P = 0.0034);Loss of disorder (P = 0.0034);
MVP		0.57
MPC		0.72
ClinPred		0.64	D
GERP RS		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.18
gMVP		0.51

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: rs760709054; hg19: chr17-42148349;