rs34901902

Variant names:

• chr12-101764859-TGTTGA-T
• rs34901902
• NM_024312.5:c.2053_2057delTCAAC

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.2053_2057delTCAAC​(p.Ser685LysfsTer61) 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 (★★). 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 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 12-101764859-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 rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.2053_2057delTCAAC	p.Ser685LysfsTer61	frameshift_variant	Exon 13 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.1972_1976delTCAAC	p.Ser658LysfsTer61	frameshift_variant	Exon 13 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.2053_2057delTCAAC	p.Ser685LysfsTer61	frameshift_variant	Exon 13 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.2053_2057delTCAAC	p.Ser685LysfsTer61	frameshift_variant	Exon 13 of 21	1	NM_024312.5	ENSP00000299314.7

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

May 23, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of mucolipidosis type III alpha (PMID: 16465621). This variant is also known as 2215_2219delACTCA. ClinVar contains an entry for this variant (Variation ID: 38417). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Nov 03, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 10, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Pathogenic:1

Dec 14, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;