rs1408113895

Positions:

• chr12-101830576-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024312.5(GNPTAB):​c.99del​(p.Ala34ProfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S33S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.556

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 351 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-101830576-CG-C is Pathogenic according to our data. Variant chr12-101830576-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101830576-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.99del	p.Ala34ProfsTer49	frameshift_variant	1/21	ENST00000299314.12
GNPTAB	XM_006719593.4	c.99del	p.Ala34ProfsTer49	frameshift_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.99del	p.Ala34ProfsTer49	frameshift_variant	1/21	1	NM_024312.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudo-Hurler polydystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Aug 29, 2017

- -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2023

This sequence change creates a premature translational stop signal (p.Ala34Profs*49) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Mucolipidosis type II (PMID: 27662472, 29872134). ClinVar contains an entry for this variant (Variation ID: 496456). For these reasons, this variant has been classified as Pathogenic. -

Mucolipidosis type II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 05, 2016

Variant summary: This c.99delC variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 34 and leads to a premature termination codon 48 amino acid downstream. It is predicted to cause a truncated or absent protein product. Mutation taster predicts this variant to be disease-causing. The variant was not observed in the large and broad cohorts of the ExAC project or ESP. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, clinical laboratories, or databases; nor evaluated for functional impact by in vivo/vitro studies. Truncations downstream of this position have been listed as disease variants by HGMD and ClinVar (e.g. Gln104Term, Gln278Term, etc). Considering all, this variant has been classified as Likely Pathogenic until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs1408113895; hg19: chr12-102224354;