rs281865035

chr12-101757654-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024312.5(GNPTAB):c.3252del(p.Pro1085ArgfsTer6) variant causes a frameshift, splice region 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPTAB NM_024312.5 frameshift, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.205

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 11 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 12-101757654-GT-G is Pathogenic according to our data. Variant chr12-101757654-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 38425.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-101757654-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.3252del	p.Pro1085ArgfsTer6	frameshift_variant, splice_region_variant	17/21	ENST00000299314.12
GNPTAB	XM_011538731.3	c.3171del	p.Pro1058ArgfsTer6	frameshift_variant, splice_region_variant	17/21
GNPTAB	XM_006719593.4	c.3252del	p.Pro1085ArgfsTer6	frameshift_variant, splice_region_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3252del	p.Pro1085ArgfsTer6	frameshift_variant, splice_region_variant	17/21	1	NM_024312.5	P1
GNPTAB	ENST00000550718.1	c.64del	p.Pro23ArgfsTer6	frameshift_variant, splice_region_variant	2/4	3
GNPTAB	ENST00000549194.1	n.118del		splice_region_variant, non_coding_transcript_exon_variant	2/3	3
GNPTAB	ENST00000549738.5	c.3del	p.Pro2ArgfsTer6	frameshift_variant, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mucolipidosis type II Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 10, 2012

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs281865035; hg19: chr12-102151432;