rs751953529

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_024312.5(GNPTAB):c.571G>A(p.Val191Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000069 in 1,449,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V191V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.61

Publications

2 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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-101786012-C-T is Pathogenic according to our data. Variant chr12-101786012-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 397556.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GNPTAB	NM_024312.5 link	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	Exon 5 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3 link	c.490G>A	p.Val164Ile	missense_variant, splice_region_variant	Exon 5 of 21		XP_011537033.1
GNPTAB	XM_006719593.4 link	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	Exon 5 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GNPTAB	ENST00000299314.12 link	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	Exon 5 of 21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000549940.5 link	c.571G>A	p.Val191Ile	missense_variant, splice_region_variant	Exon 5 of 11	1		ENSP00000449150.1
GNPTAB	ENST00000552681.1 link	c.205G>A	p.Val69Ile	missense_variant, splice_region_variant	Exon 1 of 3	1		ENSP00000449217.1
GNPTAB	ENST00000550352.1 link	n.365G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250636

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33218

American (AMR)

AF:

0.00

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101378

Other (OTH)

AF:

0.00

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Pathogenic:1

Jan 01, 2016

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

6.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.60

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.044

D;D;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.70

P;P;.

Vest4

0.20

MutPred

0.20

Loss of ubiquitination at K189 (P = 0.0954);Loss of ubiquitination at K189 (P = 0.0954);.;

MVP

0.86

MPC

0.24

ClinPred

0.56

GERP RS

5.7

PromoterAI

-0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.31

Mutation Taster

=21/79

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.84

Position offset: 0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over