rs35333334

Variant names:

• chr12-101749181-G-A
• rs35333334
• NM_024312.5:c.3613C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-101749181-G-A
• chr12-101749181-G-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_024312.5(GNPTAB):​c.3613C>T​(p.Arg1205*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000276 in 1,451,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002073351: Functional studies on skin fibroblasts have revealed a damaging effect (Kudo M et al)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1205R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GNPTAB NM_024312.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 5.60
• 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: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• mucolipidosis type III, alpha/beta

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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002073351: Functional studies on skin fibroblasts have revealed a damaging effect (Kudo M et al).; SCV001362262: Kudo_2006 measured enzymatic activity in fibroblasts derived from a patient homozygous for this mutation and found to be 4.4% of the activity in normal fibroblasts.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-101749181-G-A is Pathogenic according to our data. Variant chr12-101749181-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.3613C>T	p.Arg1205*	stop_gained	Exon 20 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.3613C>T	p.Arg1205*	stop_gained	Exon 20 of 21	ENSP00000299314.7	Q3T906-1
	GNPTAB	ENST00000917136.1		c.3634C>T	p.Arg1212*	stop_gained	Exon 20 of 21	ENSP00000587195.1
	GNPTAB	ENST00000917134.1		c.3607C>T	p.Arg1203*	stop_gained	Exon 20 of 21	ENSP00000587193.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451716 Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2 AN XY: 722954

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1102860

Other (OTH) AF: 0.00 AC: 0 AN: 60068

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Mucolipidosis type II (4)
2	-	-	Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (2)
1	-	-	Mucolipidosis (1)
1	-	-	not provided (1)
1	-	-	Pseudo-Hurler polydystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		5.6
Vest4		0.84
GERP RS		5.0
Mutation Taster		=12/188	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: rs35333334; hg19: chr12-102142959; COSMIC: COSV100172045;