12-101761122-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024312.5(GNPTAB):c.3135+5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,598,386 control chromosomes in the GnomAD database, including 251,192 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 29262 hom., cov: 32)

Exomes 𝑓: 0.55 ( 221930 hom. )

Consequence

GNPTAB
NM_024312.5 splice_region, intron

Scores

Splicing: ADA: 0.00005533

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.516

Publications

28 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

GNPTAB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-101761122-A-G is Benign according to our data. Variant chr12-101761122-A-G is described in ClinVar as Benign. ClinVar VariationId is 96121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5 link	c.3135+5T>C	splice_region_variant, intron_variant	Intron 15 of 20	ENST00000299314.12	NP_077288.2	Q3T906-1
GNPTAB	XM_011538731.3 link	c.3054+5T>C	splice_region_variant, intron_variant	Intron 15 of 20		XP_011537033.1
GNPTAB	XM_006719593.4 link	c.3135+5T>C	splice_region_variant, intron_variant	Intron 15 of 18		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12 link	c.3135+5T>C		splice_region_variant, intron_variant	Intron 15 of 20	1	NM_024312.5	ENSP00000299314.7		Q3T906-1

Frequencies

GnomAD3 genomes

AF:

0.612

AC:

92926

AN:

151904

Hom.:

29217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.730

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.552

Gnomad ASJ

AF:

0.568

Gnomad EAS

AF:

0.898

Gnomad SAS

AF:

0.645

Gnomad FIN

AF:

0.640

Gnomad MID

AF:

0.602

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.603

GnomAD2 exomes

AF:

0.599

AC:

150174

AN:

250620

AF XY:

0.596

show subpopulations

Gnomad AFR exome

AF:

0.740

Gnomad AMR exome

AF:

0.582

Gnomad ASJ exome

AF:

0.551

Gnomad EAS exome

AF:

0.905

Gnomad FIN exome

AF:

0.623

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.576

GnomAD4 exome

AF:

0.548

AC:

792261

AN:

1446364

Hom.:

221930

Cov.:

AF XY:

0.550

AC XY:

395999

AN XY:

720548

show subpopulations

African (AFR)

AF:

0.746

AC:

24700

AN:

33106

American (AMR)

AF:

0.579

AC:

25867

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.561

AC:

14593

AN:

26032

East Asian (EAS)

AF:

0.887

AC:

35134

AN:

39624

South Asian (SAS)

AF:

0.621

AC:

53342

AN:

85938

European-Finnish (FIN)

AF:

0.618

AC:

32966

AN:

53344

Middle Eastern (MID)

AF:

0.609

AC:

3502

AN:

5746

European-Non Finnish (NFE)

AF:

0.517

AC:

567355

AN:

1098076

Other (OTH)

AF:

0.582

AC:

34802

AN:

59830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

15916

31833

47749

63666

79582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16408

32816

49224

65632

82040

<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:

0.612

AC:

93037

AN:

152022

Hom.:

29262

Cov.:

AF XY:

0.617

AC XY:

45835

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.730

AC:

30269

AN:

41458

American (AMR)

AF:

0.553

AC:

8452

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

1969

AN:

3468

East Asian (EAS)

AF:

0.897

AC:

4647

AN:

5178

South Asian (SAS)

AF:

0.645

AC:

3104

AN:

4816

European-Finnish (FIN)

AF:

0.640

AC:

6754

AN:

10552

Middle Eastern (MID)

AF:

0.589

AC:

172

AN:

292

European-Non Finnish (NFE)

AF:

0.527

AC:

35804

AN:

67960

Other (OTH)

AF:

0.608

AC:

1281

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1796

3592

5389

7185

8981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<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:

0.558

Hom.:

73558

Bravo

AF:

0.613

Asia WGS

AF:

0.786

AC:

2729

AN:

3478

EpiCase

AF:

0.535

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 10, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GNPTAB c.3135+5T>C variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 72377/120336 (22256 homozygotes) at a frequency of 0.6014576, with indicates the C allele is the major allele (the allele most commonly observed in the general population). In addition, multiple clinical diagnostic laboratories/databases cite the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mucolipidosis type II

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pseudo-Hurler polydystrophy

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.2

(source)

DANN

Benign

0.60

PhyloP100

0.52

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.020

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over