rs34491309

Variant names:

• chr17-44075817-A-G
• rs34491309
• NM_138387.4:c.815A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-44075817-A-G
• chr17-44075817-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138387.4(G6PC3):​c.815A>G​(p.Gln272Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,611,722 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q272Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (40 hom.)
• Consequence: G6PC3 NM_138387.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.46
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024951696).
• BP6: Variant 17-44075817-A-G is Benign according to our data. Variant chr17-44075817-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 323470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1864/152304) while in subpopulation AFR AF = 0.0428 (1778/41550). AF 95% confidence interval is 0.0411. There are 37 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

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.815A>G	p.Gln272Arg	missense	Exon 6 of 6	NP_612396.1	Q9BUM1
	G6PC3	NM_001384165.1		c.470A>G	p.Gln157Arg	missense	Exon 6 of 6	NP_001371094.1	A0A8Q3SIG5
	G6PC3	NM_001384166.1		c.470A>G	p.Gln157Arg	missense	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.815A>G	p.Gln272Arg	missense	Exon 6 of 6	ENSP00000269097.3	Q9BUM1
	G6PC3	ENST00000588558.6	TSL:1	n.*790A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000467624.1	K7EQ13
	G6PC3	ENST00000588558.6	TSL:1	n.*790A>G		3_prime_UTR	Exon 7 of 7	ENSP00000467624.1	K7EQ13

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1865 AN: 152186 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00334 AC: 833 AN: 249548 AF XY: 0.00253

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00129 AC: 1884 AN: 1459418 Hom.: 40 Cov.: 33 AF XY: 0.00111 AC XY: 809 AN XY: 726168

African (AFR) AF: 0.0440 AC: 1472 AN: 33480

American (AMR) AF: 0.00230 AC: 103 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51002

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.0000674 AC: 75 AN: 1111978

Other (OTH) AF: 0.00303 AC: 183 AN: 60374

GnomAD4 genome AF: 0.0122 AC: 1864 AN: 152304 Hom.: 37 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74480

African (AFR) AF: 0.0428 AC: 1778 AN: 41550

American (AMR) AF: 0.00353 AC: 54 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00456 Hom.: 23

Bravo AF: 0.0140

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00422 AC: 512

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.83	L
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.14
Sift	Benign	0.28	T
Sift4G	Benign	0.29	T
Polyphen		0.18	B
Vest4		0.25
MVP		0.60
MPC		0.33
ClinPred		0.0078	T
GERP RS		4.1
Varity_R		0.067
gMVP		0.19
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs34491309; hg19: chr17-42153185;