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rs118203969

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM2PP3_ModeratePP5

The NM_138387.4(G6PC3):c.554T>C(p.Leu185Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. L185L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

G6PC3
NM_138387.4 missense

Scores

5
8
6

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.16
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS1
Transcript NM_138387.4 (G6PC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 17-44075328-T-C is Pathogenic according to our data. Variant chr17-44075328-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1038.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
G6PC3NM_138387.4 linkuse as main transcriptc.554T>C p.Leu185Pro missense_variant 5/6 ENST00000269097.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PC3ENST00000269097.9 linkuse as main transcriptc.554T>C p.Leu185Pro missense_variant 5/61 NM_138387.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;D
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.61
T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
-0.12
T
MutationAssessor
Benign
1.9
L;.
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.6
N;.
REVEL
Uncertain
0.64
Sift
Benign
0.066
T;.
Sift4G
Benign
0.21
T;T
Polyphen
0.97
D;.
Vest4
0.96
MutPred
0.87
Loss of helix (P = 0.0138);.;
MVP
0.84
MPC
1.0
ClinPred
0.77
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.89
gMVP
0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118203969; hg19: chr17-42152696; API