rs281864975

Variant names:

• chr12-101768120-C-T
• rs281864975
• NM_024312.5:c.1325G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024312.5(GNPTAB):​c.1325G>A​(p.Cys442Tyr) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 7.29
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Ambry Genetics, Orphanet
• mucolipidosis type III, alpha/beta

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

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.1325G>A	p.Cys442Tyr	missense	Exon 11 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.1325G>A	p.Cys442Tyr	missense	Exon 11 of 21	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000549940.5	TSL:1	c.1325G>A	p.Cys442Tyr	missense	Exon 11 of 11	ENSP00000449150.1	Q3T906-2
	GNPTAB	ENST00000917136.1		c.1346G>A	p.Cys449Tyr	missense	Exon 11 of 21	ENSP00000587195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.000554 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	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	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.89		Loss of catalytic residue at P443 (P = 0.3339)
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98
Mutation Taster		=4/96	disease causing

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: rs281864975; hg19: chr12-102161898;