rs769441127

chr17-44071174-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138387.4(G6PC3):c.210del(p.Phe71SerfsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: G6PC3 NM_138387.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.43

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44071174-TC-T is Pathogenic according to our data. Variant chr17-44071174-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 189782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44071174-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC3	NM_138387.4	c.210del	p.Phe71SerfsTer46	frameshift_variant	1/6	ENST00000269097.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC3	ENST00000269097.9	c.210del	p.Phe71SerfsTer46	frameshift_variant	1/6	1	NM_138387.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 249644 Hom.: 0 AF XY: 0.0000888 AC XY: 12 AN XY: 135102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000812

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461048 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000627

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Phe71Serfs*46) in the G6PC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in G6PC3 are known to be pathogenic (PMID: 19118303, 25491320). This variant is present in population databases (rs769441127, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with congenital neutropenia (PMID: 19775295, 22050868, 27577878). This variant is also known as I70fsX115 and Ile70fsX46. ClinVar contains an entry for this variant (Variation ID: 189782). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic without evidence for the classification (PMID: 19775295). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19775295, 27577878, 22050868, 34964150) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs769441127; hg19: chr17-42148542;