NM_024312.5:c.3335+1G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_024312.5(GNPTAB):c.3335+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000129 in 1,390,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.04

Publications

5 publications found

Variant links:

Genes affected

GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

GNPTAB Gene-Disease associations (from GenCC):

GNPTAB-mucolipidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mucolipidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
mucolipidosis type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp
mucolipidosis type III, alpha/beta
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp

GNPTAB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 12-101757571-C-T is Pathogenic according to our data. Variant chr12-101757571-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GNPTAB	NM_024312.5 link	c.3335+1G>A	splice_donor_variant, intron_variant	Intron 17 of 20	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3 link	c.3254+1G>A	splice_donor_variant, intron_variant	Intron 17 of 20		XP_011537033.1
GNPTAB	XM_006719593.4 link	c.3335+1G>A	splice_donor_variant, intron_variant	Intron 17 of 18		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GNPTAB	ENST00000299314.12 link	c.3335+1G>A	splice_donor_variant, intron_variant	Intron 17 of 20	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000550718.1 link	c.146+1G>A	splice_donor_variant, intron_variant	Intron 2 of 3	3		ENSP00000449557.1
GNPTAB	ENST00000549194.1 link	n.201+1G>A	splice_donor_variant, intron_variant	Intron 2 of 2	3
GNPTAB	ENST00000549738.5 link	n.86+1G>A	splice_donor_variant, intron_variant	Intron 1 of 4	4		ENSP00000450161.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152146

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251176

AF XY:

0.0000442

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1237768

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

627616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29006

American (AMR)

AF:

0.00

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24738

East Asian (EAS)

AF:

0.00

AC:

AN:

38550

South Asian (SAS)

AF:

0.000171

AC:

AN:

81702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5332

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

907908

Other (OTH)

AF:

0.0000189

AC:

AN:

52996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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

AF:

0.0000131

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type II

Pathogenic:5

Sep 11, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 13, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Homozygous missense variation in intron 17 of the GNPTAB gene was detected. The observed variant c.3335+1G>A has not been reported in the 1000 genomes and has a MAF of 0.0032% in gnomAD databases. The in silico prediction of the variant are possibly damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

May 10, 2012

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The invariant splice donor site c.3335+1G>A variant in the GNPTAB gene has been observed in individuals in homozygous/ heterozygous state affected with Mucolipidosis Type II. Experimental studies have shown that this variant disrupts mRNA splicing Kudo et al., 2006; Costain et al., 2019. This variant is reported with an allele frequency 0.003% in the gnomAD. It has been submitted in the ClinVar database as Pathogenic multiple submissions. Loss of function variants have been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Pathogenic:2

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 17 of the GNPTAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs34940801, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with clinical features of GNPTAB-related conditions (PMID: 16465621, 32651481). This variant is also known as IVS17+1G>A. ClinVar contains an entry for this variant (Variation ID: 2772). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudo-Hurler polydystrophy

Pathogenic:1

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed splice donor c.3335+1G>A variant in GNPTAB gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Mucolipidosis Type II and Type III (Pasumarthi D et al., 2020). This variant is reported with the allele frequency of 0.0032% in the gnomAD Exomes. The variant affects the GT donor splice site downstream of exon 16. The spliceAI tool predicts that this splice site variant is damaging. This variant has been reported Pathogenic in ClinVar database. The spliceAI tool predicts that this splice site variant is damaging. For these reasons, this variant has been classified as Pathogenic. -

Mucolipidosis

Pathogenic:1

Mar 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GNPTAB c.3335+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251176 control chromosomes. c.3335+1G>A has been reported in the literature in multiple individuals affected with Mucolipidosis supported by markedly elevated total serum hexosaminidase enzyme activity (example, Tiede_2005, Costain_2018, Pasumurthi_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Sep 20, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

PhyloP100

7.0

GERP RS

6.2

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over