17-44075933-A-AT

Variant names:

• chr17-44075933-A-AT
• rs797044567
• NM_138387.4:c.935dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_138387.4(G6PC3):​c.935dupT​(p.Asn313GlnfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC3 NM_138387.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.63
• Publications: 4 publications found

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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.101 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44075933-A-AT is Pathogenic according to our data. Variant chr17-44075933-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 189784.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC3	NM_138387.4	MANE Select	c.935dupT	p.Asn313GlnfsTer74	frameshift	Exon 6 of 6	NP_612396.1	Q9BUM1
	G6PC3	NM_001384165.1		c.590dupT	p.Asn198GlnfsTer74	frameshift	Exon 6 of 6	NP_001371094.1	A0A8Q3SIG5
	G6PC3	NM_001384166.1		c.590dupT	p.Asn198GlnfsTer74	frameshift	Exon 7 of 7	NP_001371095.1	A0A8Q3SIG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC3	ENST00000269097.9	TSL:1 MANE Select	c.935dupT	p.Asn313GlnfsTer74	frameshift	Exon 6 of 6	ENSP00000269097.3	Q9BUM1
	G6PC3	ENST00000588558.6	TSL:1	n.*910dupT		non_coding_transcript_exon	Exon 7 of 7	ENSP00000467624.1	K7EQ13
	G6PC3	ENST00000588558.6	TSL:1	n.*910dupT		3_prime_UTR	Exon 7 of 7	ENSP00000467624.1	K7EQ13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=1/199	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs797044567; hg19: chr17-42153301;