chr12-101764362-ATTTTC-A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024312.5(GNPTAB):​c.2550_2554delGAAAA​(p.Lys850AsnfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.337

Publications

5 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 12-101764362-ATTTTC-A is Pathogenic according to our data. Variant chr12-101764362-ATTTTC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNPTABNM_024312.5 linkc.2550_2554delGAAAA p.Lys850AsnfsTer10 frameshift_variant Exon 13 of 21 ENST00000299314.12 NP_077288.2 Q3T906-1
GNPTABXM_011538731.3 linkc.2469_2473delGAAAA p.Lys823AsnfsTer10 frameshift_variant Exon 13 of 21 XP_011537033.1
GNPTABXM_006719593.4 linkc.2550_2554delGAAAA p.Lys850AsnfsTer10 frameshift_variant Exon 13 of 19 XP_006719656.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNPTABENST00000299314.12 linkc.2550_2554delGAAAA p.Lys850AsnfsTer10 frameshift_variant Exon 13 of 21 1 NM_024312.5 ENSP00000299314.7 Q3T906-1

Frequencies

GnomAD3 genomes
AF:
0.00000660
AC:
1
AN:
151614
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000243
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000279
AC:
7
AN:
251182
AF XY:
0.0000368
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461720
Hom.:
0
AF XY:
0.0000110
AC XY:
8
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.0000580
AC:
5
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53318
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111986
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000660
AC:
1
AN:
151614
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
73994
show subpopulations
African (AFR)
AF:
0.0000243
AC:
1
AN:
41208
American (AMR)
AF:
0.00
AC:
0
AN:
15226
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5160
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4802
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10498
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67946
Other (OTH)
AF:
0.00
AC:
0
AN:
2084
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:4
Mar 22, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 01, 2016
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Oct 02, 2017
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Lys850Asnfs*10) 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). This variant is present in population databases (rs281864996, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mucolipidosis type II alpha/beta (PMID: 19634183). ClinVar contains an entry for this variant (Variation ID: 39055). For these reasons, this variant has been classified as Pathogenic. -

Mucolipidosis type II Pathogenic:2Other:1
Nov 22, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: GNPTAB c.2550_2554delGAAAA (p.Lys850AsnfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 251182 control chromosomes (gnomAD). c.2550_2554delGAAAA has been reported in the literature in homozygous and compound heterozygous individuals affected with Mucolipidosis type 2 (Liu_2016, Tappino_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Apr 13, 2023
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

A heterozygous variation in exon 13 of the GNPTAB gene detected. The observed variant c.2550_2554del has not been reported in the 1000 genomes and MAF 0.0028% in the gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 and damaging by SIFT and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic. -

-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Mucolipidosis Pathogenic:1
-
Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.34
Mutation Taster
=4/196
disease causing (ClinVar)

Splicing

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

Publications

Other links and lift over

dbSNP: rs281864996; hg19: chr12-102158140; API