14-52778458-C-T

Variant names:

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

Splicing: ADA: 0.04203

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]

GNPNAT1 links:

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
GNPNAT1	NM_198066.4 link	c.408G>A	p.Leu136Leu	splice_region_variant, synonymous_variant	Exon 6 of 6	ENST00000216410.8	NP_932332.1	Q96EK6A0A024R649
GNPNAT1	XM_005268012.4 link	c.408G>A	p.Leu136Leu	splice_region_variant, synonymous_variant	Exon 7 of 7		XP_005268069.1	Q96EK6A0A024R649
GNPNAT1	XM_006720238.4 link	c.408G>A	p.Leu136Leu	splice_region_variant, synonymous_variant	Exon 6 of 6		XP_006720301.1	Q96EK6A0A024R649
GNPNAT1	XM_047431705.1 link	c.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	UniProt
GNPNAT1	ENST00000216410.8 link	c.408G>A	p.Leu136Leu	splice_region_variant, synonymous_variant	Exon 6 of 6	1	NM_198066.4	ENSP00000216410.3	Q96EK6
GNPNAT1	ENST00000650397.1 link	c.408G>A	p.Leu136Leu	splice_region_variant, synonymous_variant	Exon 6 of 7			ENSP00000496934.1	Q96EK6
GNPNAT1	ENST00000557604.1 link	c.408G>A	p.Leu136Leu	splice_region_variant, synonymous_variant	Exon 7 of 7	3		ENSP00000452032.1	G3V4W4
GNPNAT1	ENST00000554230.5 link	c.195G>A	p.Leu65Leu	splice_region_variant, synonymous_variant	Exon 5 of 5	5		ENSP00000452310.1	G3V5E4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151970

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:

0.0000125

AC:

AN:

239056

Hom.:

AF XY:

0.0000231

AC XY:

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:

AN:

1449080

Hom.:

Cov.:

AF XY:

0.00000693

AC XY:

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:

AN:

151970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

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

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.

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