NM_138387.4:c.219-50C>G

Variant names:

• chr17-44074110-C-G
• rs148256151
• NM_138387.4:c.219-50C>G

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.219-50C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,315,042 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (4 hom.)
• Consequence: G6PC3 NM_138387.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.631
• 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, 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=-0.88).
• BP6: Variant 17-44074110-C-G is Benign according to our data. Variant chr17-44074110-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 262365.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 = 0.00352 (535/152180) while in subpopulation AFR AF = 0.0116 (482/41512). AF 95% confidence interval is 0.0108. There are 3 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC3	NM_138387.4	MANE Select	c.219-50C>G		intron	N/A	NP_612396.1
	G6PC3	NM_001384165.1		c.-127-50C>G		intron	N/A	NP_001371094.1
	G6PC3	NM_001384166.1		c.-127-50C>G		intron	N/A	NP_001371095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC3	ENST00000269097.9	TSL:1 MANE Select	c.219-50C>G		intron	N/A	ENSP00000269097.3
	G6PC3	ENST00000588558.6	TSL:1	n.*194-50C>G		intron	N/A	ENSP00000467624.1
	G6PC3	ENST00000696393.1		c.219-50C>G		intron	N/A	ENSP00000512603.1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152066 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00134 AC: 336 AN: 250586 AF XY: 0.00111

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000496

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000777 AC: 904 AN: 1162862 Hom.: 4 Cov.: 16 AF XY: 0.000730 AC XY: 433 AN XY: 592940

African (AFR) AF: 0.0117 AC: 325 AN: 27688

American (AMR) AF: 0.000654 AC: 29 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 35 AN: 24140

East Asian (EAS) AF: 0.00 AC: 0 AN: 38280

South Asian (SAS) AF: 0.000947 AC: 76 AN: 80278

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53296

Middle Eastern (MID) AF: 0.000770 AC: 4 AN: 5198

European-Non Finnish (NFE) AF: 0.000442 AC: 371 AN: 839076

Other (OTH) AF: 0.00113 AC: 57 AN: 50548

GnomAD4 genome AF: 0.00352 AC: 535 AN: 152180 Hom.: 3 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74398

African (AFR) AF: 0.0116 AC: 482 AN: 41512

American (AMR) AF: 0.000524 AC: 8 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.00415

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.049
DANN	Benign	0.55
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148256151; hg19: chr17-42151478;