12-101830658-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024312.5(GNPTAB):c.18G>A(p.Leu6Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,604,472 control chromosomes in the GnomAD database, including 11,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.097 ( 870 hom., cov: 31)

Exomes 𝑓: 0.12 ( 10614 hom. )

Consequence

GNPTAB
NM_024312.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.268

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 12-101830658-C-T is Benign according to our data. Variant chr12-101830658-C-T is described in ClinVar as Benign. ClinVar VariationId is 96118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.268 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 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.18G>A	p.Leu6Leu	synonymous	Exon 1 of 21	NP_077288.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.18G>A	p.Leu6Leu	synonymous	Exon 1 of 21	ENSP00000299314.7	Q3T906-1
GNPTAB	ENST00000549940.5	TSL:1	c.18G>A	p.Leu6Leu	synonymous	Exon 1 of 11	ENSP00000449150.1	Q3T906-2
GNPTAB	ENST00000392919.4	TSL:1	c.18G>A	p.Leu6Leu	synonymous	Exon 1 of 3	ENSP00000376651.4	Q9BUA5

Frequencies

GnomAD3 genomes

AF:

0.0975

AC:

14805

AN:

151838

Hom.:

870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0350

Gnomad AMI

AF:

0.108

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.0816

Gnomad FIN

AF:

0.0877

Gnomad MID

AF:

0.185

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.119

GnomAD2 exomes

AF:

0.116

AC:

28577

AN:

246864

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.172

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.0809

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.117

AC:

170650

AN:

1452516

Hom.:

10614

Cov.:

AF XY:

0.116

AC XY:

83901

AN XY:

723076

show subpopulations

African (AFR)

AF:

0.0314

AC:

1043

AN:

33248

American (AMR)

AF:

0.172

AC:

7672

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3090

AN:

25988

East Asian (EAS)

AF:

0.167

AC:

6591

AN:

39560

South Asian (SAS)

AF:

0.0839

AC:

7220

AN:

86036

European-Finnish (FIN)

AF:

0.0857

AC:

4545

AN:

53060

Middle Eastern (MID)

AF:

0.166

AC:

951

AN:

5732

European-Non Finnish (NFE)

AF:

0.120

AC:

132264

AN:

1104362

Other (OTH)

AF:

0.121

AC:

7274

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

6327

12654

18981

25308

31635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4806

9612

14418

19224

24030

<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:

0.0974

AC:

14805

AN:

151956

Hom.:

870

Cov.:

AF XY:

0.0961

AC XY:

7140

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0349

AC:

1448

AN:

41516

American (AMR)

AF:

0.142

AC:

2162

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

437

AN:

3464

East Asian (EAS)

AF:

0.165

AC:

847

AN:

5144

South Asian (SAS)

AF:

0.0827

AC:

399

AN:

4822

European-Finnish (FIN)

AF:

0.0877

AC:

927

AN:

10572

Middle Eastern (MID)

AF:

0.185

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.121

AC:

8186

AN:

67876

Other (OTH)

AF:

0.117

AC:

247

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

660

1320

1981

2641

3301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.114

Hom.:

792

Bravo

AF:

0.103

Asia WGS

AF:

0.105

AC:

365

AN:

3478

EpiCase

AF:

0.120

EpiControl

AF:

0.116

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Mucolipidosis type II (3)

not specified (2)

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

-0.56

CADD

Benign

6.3

(source)

DANN

Benign

0.84

PhyloP100

0.27

PromoterAI

0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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