rs34901902

chr12-101764859-TGTTGA-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_024312.5(GNPTAB):c.2053_2057del(p.Ser685LysfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S685S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.88

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-101764859-TGTTGA-T is Pathogenic according to our data. Variant chr12-101764859-TGTTGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101764859-TGTTGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.2053_2057del	p.Ser685LysfsTer61	frameshift_variant	13/21	ENST00000299314.12
GNPTAB	XM_006719593.4	c.2053_2057del	p.Ser685LysfsTer61	frameshift_variant	13/19
GNPTAB	XM_011538731.3	c.1972_1976del	p.Ser658LysfsTer61	frameshift_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.2053_2057del	p.Ser685LysfsTer61	frameshift_variant	13/21	1	NM_024312.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

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	Jan 16, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38417). This variant is also known as 2215_2219delACTCA. This premature translational stop signal has been observed in individual(s) with clinical features of mucolipidosis type III alpha (PMID: 16465621). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser685Lysfs*61) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2021

The c.2053_2057delTCAAC (p.S685Kfs*61) alteration, located in exon 13 (coding exon 13) of the GNPTAB gene, consists of a deletion of 5 nucleotides from position 2053 to 2057, causing a translational frameshift with a predicted alternate stop codon after 61 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in trans with a pathogenic splice mutation in an individual with a mucolipodosis type III alpha phenotype (Kudo, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

Mucopolysaccharidosis, MPS-III-A Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 10, 2012

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34901902; hg19: chr12-102158637;