14-52778360-C-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198066.4(GNPNAT1):c.506G>T(p.Gly169Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,605,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GNPNAT1
NM_198066.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPNAT1	NM_198066.4 link	c.506G>T	p.Gly169Val	missense_variant	Exon 6 of 6	ENST00000216410.8	NP_932332.1	Q96EK6A0A024R649
GNPNAT1	XM_005268012.4 link	c.506G>T	p.Gly169Val	missense_variant	Exon 7 of 7		XP_005268069.1	Q96EK6A0A024R649
GNPNAT1	XM_006720238.4 link	c.506G>T	p.Gly169Val	missense_variant	Exon 6 of 6		XP_006720301.1	Q96EK6A0A024R649
GNPNAT1	XM_047431705.1 link	c.506G>T	p.Gly169Val	missense_variant	Exon 7 of 7		XP_047287661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNPNAT1	ENST00000216410.8 link	c.506G>T	p.Gly169Val	missense_variant	Exon 6 of 6	1	NM_198066.4	ENSP00000216410.3	Q96EK6
GNPNAT1	ENST00000650397.1 link	c.506G>T	p.Gly169Val	missense_variant	Exon 6 of 7			ENSP00000496934.1	Q96EK6
GNPNAT1	ENST00000554230.5 link	c.293G>T	p.Gly98Val	missense_variant	Exon 5 of 5	5		ENSP00000452310.1	G3V5E4
GNPNAT1	ENST00000557604.1 link	c.*15G>T		downstream_gene_variant		3		ENSP00000452032.1	G3V4W4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

246086

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453650

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.506G>T (p.G169V) alteration is located in exon 6 (coding exon 5) of the GNPNAT1 gene. This alteration results from a G to T substitution at nucleotide position 506, causing the glycine (G) at amino acid position 169 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

4.4

H;H;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.4

D;.;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;D;.

Vest4

0.77

MutPred

0.88

Gain of methylation at K166 (P = 0.1348);Gain of methylation at K166 (P = 0.1348);.;

MVP

0.91

MPC

1.4

ClinPred

1.0

GERP RS

4.8

Varity_R

0.88

gMVP

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over