14-52778458-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_198066.4(GNPNAT1):​c.408G>A​(p.Leu136Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,601,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GNPNAT1
NM_198066.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.04203
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP7
Synonymous conserved (PhyloP=1.53 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNPNAT1NM_198066.4 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 6 of 6 ENST00000216410.8 NP_932332.1 Q96EK6A0A024R649
GNPNAT1XM_005268012.4 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 7 of 7 XP_005268069.1 Q96EK6A0A024R649
GNPNAT1XM_006720238.4 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 6 of 6 XP_006720301.1 Q96EK6A0A024R649
GNPNAT1XM_047431705.1 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 7 of 7 XP_047287661.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNPNAT1ENST00000216410.8 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 6 of 6 1 NM_198066.4 ENSP00000216410.3 Q96EK6
GNPNAT1ENST00000650397.1 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 6 of 7 ENSP00000496934.1 Q96EK6
GNPNAT1ENST00000557604.1 linkc.408G>A p.Leu136Leu splice_region_variant, synonymous_variant Exon 7 of 7 3 ENSP00000452032.1 G3V4W4
GNPNAT1ENST00000554230.5 linkc.195G>A p.Leu65Leu splice_region_variant, synonymous_variant Exon 5 of 5 5 ENSP00000452310.1 G3V5E4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151970
Hom.:
0
Cov.:
32
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:
0.0000125
AC:
3
AN:
239056
Hom.:
0
AF XY:
0.0000231
AC XY:
3
AN XY:
129778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000272
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000552
AC:
8
AN:
1449080
Hom.:
0
Cov.:
28
AF XY:
0.00000693
AC XY:
5
AN XY:
720998
show subpopulations
Gnomad4 AFR exome
AF:
0.0000307
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000632
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151970
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74234
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
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.00000756
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 29, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with GNPNAT1-related conditions. This variant is present in population databases (rs778581062, gnomAD 0.002%). This sequence change affects codon 136 of the GNPNAT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GNPNAT1 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
CADD
Benign
13
DANN
Benign
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.042
dbscSNV1_RF
Benign
0.28
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: rs778581062; hg19: chr14-53245176; API