rs3815076

Variant names:

• chr17-44074735-G-A
• rs3815076
• NM_138387.4:c.381G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44074735-G-A
• chr17-44074735-G-C
• chr17-44074735-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138387.4(G6PC3):​c.381G>A​(p.Thr127Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,860 control chromosomes in the GnomAD database, including 22,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2707 hom., cov: 32)
  • Exomes 𝑓: 0.11 (20019 hom.)
• Consequence: G6PC3 NM_138387.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.41
• Publications: 23 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 17-44074735-G-A is Benign according to our data. Variant chr17-44074735-G-A is described in ClinVar as Benign. ClinVar VariationId is 262366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

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.381G>A	p.Thr127Thr	synonymous	Exon 3 of 6	NP_612396.1	Q9BUM1
	G6PC3	NM_001384165.1		c.36G>A	p.Thr12Thr	synonymous	Exon 3 of 6	NP_001371094.1	A0A8Q3SIG5
	G6PC3	NM_001384166.1		c.36G>A	p.Thr12Thr	synonymous	Exon 4 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.381G>A	p.Thr127Thr	synonymous	Exon 3 of 6	ENSP00000269097.3	Q9BUM1
	G6PC3	ENST00000588558.6	TSL:1	n.*356G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000467624.1	K7EQ13
	G6PC3	ENST00000588558.6	TSL:1	n.*356G>A		3_prime_UTR	Exon 4 of 7	ENSP00000467624.1	K7EQ13

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20442 AN: 152038 Hom.: 2697 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.189 AC: 47566 AN: 251064 AF XY: 0.178

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.723

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0705

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.110 AC: 160228 AN: 1461704 Hom.: 20019 Cov.: 33 AF XY: 0.111 AC XY: 80722 AN XY: 727148

African (AFR) AF: 0.106 AC: 3535 AN: 33478

American (AMR) AF: 0.380 AC: 16960 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3313 AN: 26132

East Asian (EAS) AF: 0.723 AC: 28684 AN: 39688

South Asian (SAS) AF: 0.185 AC: 15999 AN: 86248

European-Finnish (FIN) AF: 0.131 AC: 7010 AN: 53390

Middle Eastern (MID) AF: 0.108 AC: 621 AN: 5768

European-Non Finnish (NFE) AF: 0.0683 AC: 75910 AN: 1111924

Other (OTH) AF: 0.136 AC: 8196 AN: 60388

GnomAD4 genome AF: 0.135 AC: 20473 AN: 152156 Hom.: 2707 Cov.: 32 AF XY: 0.145 AC XY: 10750 AN XY: 74376

African (AFR) AF: 0.108 AC: 4468 AN: 41536

American (AMR) AF: 0.280 AC: 4272 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 447 AN: 3466

East Asian (EAS) AF: 0.727 AC: 3747 AN: 5154

South Asian (SAS) AF: 0.201 AC: 969 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1376 AN: 10592

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0709 AC: 4818 AN: 67994

Other (OTH) AF: 0.131 AC: 276 AN: 2110

Alfa AF: 0.102 Hom.: 3424

Bravo AF: 0.148

Asia WGS AF: 0.419 AC: 1452 AN: 3478

EpiCase AF: 0.0720

EpiControl AF: 0.0775

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.51
DANN	Benign	0.78
PhyloP100		-5.4
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs3815076; hg19: chr17-42152103; COSMIC: COSV52242161; COSMIC: COSV52242161;