rs398124399

chr12-101780573-ACTGT-A

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.616_619del(p.Thr206TyrfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,609,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.82

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-101780573-ACTGT-A is Pathogenic according to our data. Variant chr12-101780573-ACTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 38432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101780573-ACTGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.616_619del	p.Thr206TyrfsTer6	frameshift_variant	6/21	ENST00000299314.12
GNPTAB	XM_006719593.4	c.616_619del	p.Thr206TyrfsTer6	frameshift_variant	6/19
GNPTAB	XM_011538731.3	c.535_538del	p.Thr179TyrfsTer6	frameshift_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.616_619del	p.Thr206TyrfsTer6	frameshift_variant	6/21	1	NM_024312.5	P1
GNPTAB	ENST00000549940.5	c.616_619del	p.Thr206TyrfsTer6	frameshift_variant	6/11	1
GNPTAB	ENST00000552681.1	c.250_253del	p.Thr84TyrfsTer6	frameshift_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251156 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1457532 Hom.: 0 AF XY: 0.00000827 AC XY: 6 AN XY: 725470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

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: 9.02e-7

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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: 0.0000508 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change creates a premature translational stop signal (p.Thr206Tyrfs*6) 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 present in population databases (rs398124399, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with mucolipidosis II and III (PMID: 16465621, 24798265). This variant is also known as FS211X (type 1), 773_776delCAGA. ClinVar contains an entry for this variant (Variation ID: 38432). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 21, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as FS211X; This variant is associated with the following publications: (PMID: 18190596, 16465621, 30882951, 24798265) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2013	- -

Mucolipidosis type II Pathogenic:2

Pathogenic, no assertion criteria provided	curation	GeneReviews	May 10, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Mucolipidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 22, 2018

Variant summary: GNPTAB c.616_619delACAG (p.Thr206TyrfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1090C>T (p.Arg364X), c.1123C>T (p.Arg375X), c.1581delC (p.Cys528fsX19)). The variant allele was found at a frequency of 4.9e-05 in 245984 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GNPTAB causing Mucolipidosis (4.9e-05 vs 2.20e-03), allowing no conclusion about variant significance. c.616_619delACAG has been reported in the literature in two individuals affected with Mucolipidosis type 2 (Kudo 2006). These data indicate that the variant may be associated with disease. This publication also reports experimental evidence evaluating an impact on protein function by measuring N-acetylglucosamine-phosphotransferase activity in cell lysates from fibroblasts or lymphoblasts derived from subjects. The most pronounced variant effect results in <1% of normal enzymatic activity. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs281865024; hg19: chr12-102174351;