rs281864953

Variant names:

• chr12-101790019-C-A
• rs281864953
• NM_024312.5:c.242G>T
• GNPTAB p.Trp81Leu

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_024312.5(GNPTAB):​c.242G>T​(p.Trp81Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003440997: Experimental studies have shown that this missense change affects GNPTAB function (PMID:24375680, 25505245).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.49
• Publications: 8 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• mucolipidosis type III, alpha/beta

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

LOC124903105 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003440997: Experimental studies have shown that this missense change affects GNPTAB function (PMID: 24375680, 25505245).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 12-101790019-C-A is Pathogenic according to our data. Variant chr12-101790019-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 39053.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024312.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	NM_024312.5	MANE Select	c.242G>T	p.Trp81Leu	missense	Exon 3 of 21	NP_077288.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.242G>T	p.Trp81Leu	missense	Exon 3 of 21	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000549940.5	TSL:1	c.242G>T	p.Trp81Leu	missense	Exon 3 of 11	ENSP00000449150.1	Q3T906-2
	GNPTAB	ENST00000917136.1		c.242G>T	p.Trp81Leu	missense	Exon 3 of 21	ENSP00000587195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (1)
-	-	-	Pseudo-Hurler polydystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.96
gMVP		0.88
Mutation Taster		=49/51	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs281864953;

hg19: chr12-102183797;