Genetic Variant GNPNAT1:p.Gly64Glu (chr14-52783449-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_198066.4(GNPNAT1):c.191G>A(p.Gly64Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G64A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GNPNAT1
NM_198066.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.37

Publications

0 publications found

Variant links:

Genes affected

GNPNAT1 (HGNC:19980): (glucosamine-phosphate N-acetyltransferase 1) Enables identical protein binding activity. Predicted to be involved in UDP-N-acetylglucosamine biosynthetic process. Predicted to act upstream of or within cellular response to leukemia inhibitory factor. Predicted to be located in late endosome. Predicted to be active in Golgi apparatus; endoplasmic reticulum; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

GNPNAT1 Gene-Disease associations (from GenCC):

osteochondrodysplasia
Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

GNPNAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.3296 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to osteochondrodysplasia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPNAT1	NM_198066.4 link	c.191G>A	p.Gly64Glu	missense_variant	Exon 3 of 6	ENST00000216410.8	NP_932332.1	Q96EK6A0A024R649
GNPNAT1	XM_005268012.4 link	c.191G>A	p.Gly64Glu	missense_variant	Exon 4 of 7		XP_005268069.1	Q96EK6A0A024R649
GNPNAT1	XM_006720238.4 link	c.191G>A	p.Gly64Glu	missense_variant	Exon 3 of 6		XP_006720301.1	Q96EK6A0A024R649
GNPNAT1	XM_047431705.1 link	c.191G>A	p.Gly64Glu	missense_variant	Exon 4 of 7		XP_047287661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPNAT1	ENST00000216410.8 link	c.191G>A	p.Gly64Glu	missense_variant	Exon 3 of 6	1	NM_198066.4	ENSP00000216410.3		Q96EK6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458698

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725790

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.00

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109516

Other (OTH)

AF:

0.00

AC:

AN:

60238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Pathogenic

3.2

M;M;.

PhyloP100

6.4

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.9

D;.;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0030

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.82

MutPred

0.76

Gain of solvent accessibility (P = 0.0246);Gain of solvent accessibility (P = 0.0246);Gain of solvent accessibility (P = 0.0246);

MVP

0.81

MPC

1.4

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.89

Mutation Taster

=205/95

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over