rs113416399

Variant names:

• chr17-44076045-T-C
• rs113416399
• NM_138387.4:c.*2T>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.*2T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,612,470 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (90 hom.)
• Consequence: G6PC3 NM_138387.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.440
• 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-44076045-T-C is Benign according to our data. Variant chr17-44076045-T-C is described in ClinVar as Benign. ClinVar VariationId is 211056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00691 (1052/152312) while in subpopulation NFE AF = 0.0127 (863/68022). AF 95% confidence interval is 0.012. There are 4 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.*2T>C		3_prime_UTR	Exon 6 of 6	NP_612396.1
	G6PC3	NM_001384165.1		c.*2T>C		3_prime_UTR	Exon 6 of 6	NP_001371094.1
	G6PC3	NM_001384166.1		c.*2T>C		3_prime_UTR	Exon 7 of 7	NP_001371095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC3	ENST00000269097.9	TSL:1 MANE Select	c.*2T>C		3_prime_UTR	Exon 6 of 6	ENSP00000269097.3
	G6PC3	ENST00000588558.6	TSL:1	n.*1018T>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000467624.1
	G6PC3	ENST00000588558.6	TSL:1	n.*1018T>C		3_prime_UTR	Exon 7 of 7	ENSP00000467624.1

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1052 AN: 152194 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00643 AC: 1611 AN: 250448 AF XY: 0.00630

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00179

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.0106 AC: 15485 AN: 1460158 Hom.: 90 Cov.: 33 AF XY: 0.0105 AC XY: 7613 AN XY: 726528

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00304 AC: 136 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00250 AC: 216 AN: 86236

European-Finnish (FIN) AF: 0.00234 AC: 121 AN: 51762

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0129 AC: 14363 AN: 1111978

Other (OTH) AF: 0.00924 AC: 558 AN: 60380

GnomAD4 genome AF: 0.00691 AC: 1052 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00615 AC XY: 458 AN XY: 74482

African (AFR) AF: 0.00229 AC: 95 AN: 41568

American (AMR) AF: 0.00327 AC: 50 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0127 AC: 863 AN: 68022

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00909 Hom.: 4

Bravo AF: 0.00703

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.00948

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.72
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113416399; hg19: chr17-42153413;