17-44075780-GGC-CGA

Variant names:

• chr17-44075780-GGC-CGA
• NM_138387.4:c.778_780delGGCinsCGA
• G6PC3 p.Gly260Arg

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Very_Strong PM1

The NM_138387.4(G6PC3):​c.778_780delGGCinsCGA​(p.Gly260Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC3 NM_138387.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.73
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_138387.4 (G6PC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_138387.4

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.778_780delGGCinsCGA	p.Gly260Arg	missense	N/A	NP_612396.1	Q9BUM1
	G6PC3	NM_001384165.1		c.433_435delGGCinsCGA	p.Gly145Arg	missense	N/A	NP_001371094.1	A0A8Q3SIG5
	G6PC3	NM_001384166.1		c.433_435delGGCinsCGA	p.Gly145Arg	missense	N/A	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.778_780delGGCinsCGA	p.Gly260Arg	missense	N/A	ENSP00000269097.3	Q9BUM1
	G6PC3	ENST00000588558.6	TSL:1	n.*753_*755delGGCinsCGA		non_coding_transcript_exon	Exon 7 of 7	ENSP00000467624.1	K7EQ13
	G6PC3	ENST00000588558.6	TSL:1	n.*753_*755delGGCinsCGA		3_prime_UTR	Exon 7 of 7	ENSP00000467624.1	K7EQ13

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

hg19: chr17-42153148;