rs281864961

Variant names:

• chr12-101780563-GCCCCT-G
• rs281864961
• NM_024312.5:c.625_629delAGGGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024312.5(GNPTAB):​c.625_629delAGGGG​(p.Arg209LeufsTer6) variant causes a frameshift change. 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: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 5.88

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 12 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 12-101780563-GCCCCT-G is Pathogenic according to our data. Variant chr12-101780563-GCCCCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39084.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-101780563-GCCCCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.625_629delAGGGG	p.Arg209LeufsTer6	frameshift_variant	Exon 6 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.544_548delAGGGG	p.Arg182LeufsTer6	frameshift_variant	Exon 6 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.625_629delAGGGG	p.Arg209LeufsTer6	frameshift_variant	Exon 6 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.625_629delAGGGG	p.Arg209LeufsTer6	frameshift_variant	Exon 6 of 21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000549940.5	c.625_629delAGGGG	p.Arg209LeufsTer6	frameshift_variant	Exon 6 of 11	1		ENSP00000449150.1
GNPTAB	ENST00000552681.1	c.259_263delAGGGG	p.Arg87LeufsTer6	frameshift_variant	Exon 2 of 3	1		ENSP00000449217.1

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: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucolipidosis type II Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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: rs281864961; hg19: chr12-102174341;