chr12-101757311-C-G

Position:

chr12-101757311-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_024312.5(GNPTAB):c.3336-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000196 in 1,530,022 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 5.65

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025987802 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-101757311-C-G is Pathogenic according to our data. Variant chr12-101757311-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101757311-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
GNPTAB	NM_024312.5 linkuse as main transcript	c.3336-1G>C	splice_acceptor_variant, intron_variant	ENST00000299314.12	NP_077288.2	Q3T906-1
GNPTAB	XM_011538731.3 linkuse as main transcript	c.3255-1G>C	splice_acceptor_variant, intron_variant		XP_011537033.1
GNPTAB	XM_006719593.4 linkuse as main transcript	c.3336-1G>C	splice_acceptor_variant, intron_variant		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
GNPTAB	ENST00000299314.12 linkuse as main transcript	c.3336-1G>C	splice_acceptor_variant, intron_variant	1	NM_024312.5	ENSP00000299314.7	Q3T906-1
GNPTAB	ENST00000550718.1 linkuse as main transcript	c.147-1G>C	splice_acceptor_variant, intron_variant	3		ENSP00000449557.1	H0YIK3
GNPTAB	ENST00000549194.1 linkuse as main transcript	n.202-1G>C	splice_acceptor_variant, intron_variant	3
GNPTAB	ENST00000549738.5 linkuse as main transcript	n.87-1G>C	splice_acceptor_variant, intron_variant	4		ENSP00000450161.1	H0YIU2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1378002

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690006

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000193

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type II

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor 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). Disruption of this splice site has been observed in individuals with mucolipidosis type II and III (PMID: 19617216, 32651481). ClinVar contains an entry for this variant (Variation ID: 41257). 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. -

Mucolipidosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 20, 2020

Variant summary: GNPTAB c.3336-1G>C 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: Two predict the variant abolishes a 5 splicing donor site. Three predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247798 control chromosomes (gnomAD). c.3336-1G>C has been reported in the literature in an individual affected with Mucolipidosis Intermediate phenotype (Cathey_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another nucleotide change (c.3336-1G>A) in the same position has been noted in the HGMD database. 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 likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.99

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