rs587777914

Positions:

• chr12-101757576-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_024312.5(GNPTAB):​c.3330_3331insA​(p.Tyr1111IlefsTer2) 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 not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.531

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.3330_3331insA	p.Tyr1111IlefsTer2	frameshift_variant	17/21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_006719593.4	c.3330_3331insA	p.Tyr1111IlefsTer2	frameshift_variant	17/19		XP_006719656.1
GNPTAB	XM_011538731.3	c.3249_3250insA	p.Tyr1084IlefsTer2	frameshift_variant	17/21		XP_011537033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3330_3331insA	p.Tyr1111IlefsTer2	frameshift_variant	17/21	1	NM_024312.5	ENSP00000299314	P1
GNPTAB	ENST00000550718.1	c.142_143insA	p.Tyr49IlefsTer2	frameshift_variant	2/4	3		ENSP00000449557
GNPTAB	ENST00000549194.1	n.196_197insA		non_coding_transcript_exon_variant	2/3	3
GNPTAB	ENST00000549738.5	c.81_82insA	p.Tyr28IlefsTer2	frameshift_variant, NMD_transcript_variant	1/5	4		ENSP00000450161

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1309072 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 659530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Mucolipidosis type II Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs281865014; hg19: chr12-102151354;