rs34946266

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_024312.5(GNPTAB):c.569A>T(p.Asp190Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,604,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 missense, splice_region

Scores

Splicing: ADA: 0.04754

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 3.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-101786014-T-A is Pathogenic according to our data. Variant chr12-101786014-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101786014-T-A is described in Lovd as [Pathogenic]. Variant chr12-101786014-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GNPTAB	NM_024312.5 linkuse as main transcript	c.569A>T	p.Asp190Val	missense_variant, splice_region_variant	5/21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3 linkuse as main transcript	c.488A>T	p.Asp163Val	missense_variant, splice_region_variant	5/21		XP_011537033.1
GNPTAB	XM_006719593.4 linkuse as main transcript	c.569A>T	p.Asp190Val	missense_variant, splice_region_variant	5/19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12 linkuse as main transcript	c.569A>T	p.Asp190Val	missense_variant, splice_region_variant	5/21	1	NM_024312.5	ENSP00000299314	P1	Q3T906-1
GNPTAB	ENST00000549940.5 linkuse as main transcript	c.569A>T	p.Asp190Val	missense_variant, splice_region_variant	5/11	1		ENSP00000449150		Q3T906-2
GNPTAB	ENST00000552681.1 linkuse as main transcript	c.203A>T	p.Asp68Val	missense_variant, splice_region_variant	1/3	1		ENSP00000449217
GNPTAB	ENST00000550352.1 linkuse as main transcript	n.363A>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251058

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135718

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000620

AC:

AN:

1452618

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723364

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000725

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type II

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PP2, PP3, PP4, PP5 -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 20, 2020	- -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 190 of the GNPTAB protein (p.Asp190Val). This variant is present in population databases (rs34946266, gnomAD 0.0009%). This missense change has been observed in individual(s) with mucolipidoses (PMID: 16465621, 19617216). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38431). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect GNPTAB function (PMID: 16465621, 19617216). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mucopolysaccharidosis, MPS-III-A

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 10, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

T;.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.1

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.010

D;D;D

Sift4G

Benign

0.12

T;T;D

Polyphen

0.0050

B;B;.

Vest4

0.54

MutPred

0.72

Loss of disorder (P = 0.0324);Loss of disorder (P = 0.0324);.;

MVP

0.81

MPC

0.34

ClinPred

0.50

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.048

dbscSNV1_RF

Benign

0.66

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.96

Position offset: 2

DS_DL_spliceai

0.60

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over