chr12-101761122-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: 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

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.

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.3135+5T>C		splice_region intron	N/A	NP_077288.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.3135+5T>C	splice_region intron	N/A	ENSP00000299314.7	Q3T906-1
GNPTAB	ENST00000917136.1		c.3156+5T>C	splice_region intron	N/A	ENSP00000587195.1
GNPTAB	ENST00000917134.1		c.3129+5T>C	splice_region intron	N/A	ENSP00000587193.1

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Mucolipidosis type II (3)

Pseudo-Hurler polydystrophy (2)

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over