12-101757571-C-T

Position:

chr12-101757571-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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:9

Conservation

PhyloP100: 7.04

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 links:

GNPTAB (HGNC:):

GNPTAB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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.

PM2

Very rare variant in population databases, with high coverage;

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
GNPTAB	NM_024312.5 linkuse as main transcript	c.3335+1G>A	splice_donor_variant, intron_variant	ENST00000299314.12	NP_077288.2	Q3T906-1
GNPTAB	XM_011538731.3 linkuse as main transcript	c.3254+1G>A	splice_donor_variant, intron_variant		XP_011537033.1
GNPTAB	XM_006719593.4 linkuse as main transcript	c.3335+1G>A	splice_donor_variant, intron_variant		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
GNPTAB	ENST00000299314.12 linkuse as main transcript	c.3335+1G>A	splice_donor_variant, intron_variant	1	NM_024312.5	ENSP00000299314.7	Q3T906-1
GNPTAB	ENST00000550718.1 linkuse as main transcript	c.146+1G>A	splice_donor_variant, intron_variant	3		ENSP00000449557.1	H0YIK3
GNPTAB	ENST00000549194.1 linkuse as main transcript	n.201+1G>A	splice_donor_variant, intron_variant	3
GNPTAB	ENST00000549738.5 linkuse as main transcript	n.86+1G>A	splice_donor_variant, intron_variant	4		ENSP00000450161.1	H0YIU2

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

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251176

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135800

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:

0.000261

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000171

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000110

Gnomad4 OTH exome

AF:

0.0000189

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74454

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:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type II

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 13, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 11, 2020	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	May 10, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2023	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). Studies have shown that disruption of this splice site is associated with altered splicing resulting in skipping of exon 17 (PMID: 16200072, 16465621). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -

Mucolipidosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 05, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

GERP RS

6.2

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

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