rs201700844

Positions:

• chr17-44075802-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_138387.4(G6PC3):​c.800C>G​(p.Ser267Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000906 in 1,611,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: G6PC3 NM_138387.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.00

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_138387.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3593421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC3	NM_138387.4	c.800C>G	p.Ser267Cys	missense_variant	6/6	ENST00000269097.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC3	ENST00000269097.9	c.800C>G	p.Ser267Cys	missense_variant	6/6	1	NM_138387.4	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249590 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000856 AC: 125 AN: 1459498 Hom.: 0 Cov.: 33 AF XY: 0.0000964 AC XY: 70 AN XY: 726202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74498

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000227 Hom.: 1

Bravo AF: 0.000155

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 22, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 267 of the G6PC3 protein (p.Ser267Cys). This variant is present in population databases (rs201700844, gnomAD 0.01%). 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: 570187). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.14
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.53	D;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	-0.00030	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.13	T;.
Sift4G	Benign	0.075	T;T
Polyphen		0.97	D;.
Vest4		0.67
MutPred		0.55		Gain of catalytic residue at S267 (P = 0.1098);.;
MVP		0.89
MPC		0.31
ClinPred		0.23	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.70

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: rs201700844; hg19: chr17-42153170;