rs281865017

Variant names:

• chr12-101757217-G-GT
• rs281865017
• NM_024312.5:c.3428dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024312.5(GNPTAB):​c.3428dupA​(p.Asn1143LysfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000043 in 1,396,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1143N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.77
• Publications: 4 publications found

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]

GNPTAB Gene-Disease associations (from GenCC):

• GNPTAB-mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucolipidosis type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• mucolipidosis type III, alpha/beta

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 12-101757217-G-GT is Pathogenic according to our data. Variant chr12-101757217-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 39072.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.3428dupA	p.Asn1143LysfsTer3	frameshift_variant	Exon 18 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.3347dupA	p.Asn1116LysfsTer3	frameshift_variant	Exon 18 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.3428dupA	p.Asn1143LysfsTer3	frameshift_variant	Exon 18 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3428dupA	p.Asn1143LysfsTer3	frameshift_variant	Exon 18 of 21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000550718.1	c.239dupA	p.Asn80fs	frameshift_variant	Exon 3 of 4	3		ENSP00000449557.1
GNPTAB	ENST00000549194.1	n.294dupA		non_coding_transcript_exon_variant	Exon 3 of 3	3
GNPTAB	ENST00000549738.5	n.179dupA		non_coding_transcript_exon_variant	Exon 2 of 5	4		ENSP00000450161.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1396862 Hom.: 0 Cov.: 25 AF XY: 0.00000429 AC XY: 3 AN XY: 698644

African (AFR) AF: 0.00 AC: 0 AN: 32240

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 84276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 9.49e-7 AC: 1 AN: 1053558

Other (OTH) AF: 0.00 AC: 0 AN: 58298

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as c.3428_3429insA. This premature translational stop signal has been observed in individual(s) with mucolipidosis II (PMID: 19197337). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1143Lysfs*3) 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). ClinVar contains an entry for this variant (Variation ID: 39072). For these reasons, this variant has been classified as Pathogenic.

Mucolipidosis type II Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs281865017; hg19: chr12-102150995;