12-101830658-C-T

Position:

chr12-101830658-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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:

GNPTAB (HGNC:):

GNPTAB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 96118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101830658-C-T is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTAB	NM_024312.5 linkuse as main transcript	c.18G>A	p.Leu6Leu	synonymous_variant	1/21	ENST00000299314.12	NP_077288.2	Q3T906-1
GNPTAB	XM_006719593.4 linkuse as main transcript	c.18G>A	p.Leu6Leu	synonymous_variant	1/19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12 linkuse as main transcript	c.18G>A	p.Leu6Leu	synonymous_variant	1/21	1	NM_024312.5	ENSP00000299314.7		Q3T906-1

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

GnomAD3 exomes

AF:

0.116

AC:

28577

AN:

246864

Hom.:

1785

AF XY:

0.114

AC XY:

15317

AN XY:

134074

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 SAS exome

AF:

0.0817

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

Gnomad4 AFR exome

AF:

0.0314

Gnomad4 AMR exome

AF:

0.172

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.167

Gnomad4 SAS exome

AF:

0.0839

Gnomad4 FIN exome

AF:

0.0857

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.0974

AC:

14805

AN:

151956

Hom.:

870

Cov.:

AF XY:

0.0961

AC XY:

7140

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0349

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.126

Gnomad4 EAS

AF:

0.165

Gnomad4 SAS

AF:

0.0827

Gnomad4 FIN

AF:

0.0877

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.114

Hom.:

591

Bravo

AF:

0.103

Asia WGS

AF:

0.105

AC:

365

AN:

3478

EpiCase

AF:

0.120

EpiControl

AF:

0.116

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2016	Variant summary: The GNPTAB c.18G>A (p.Leu6Leu) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant may alter ESE binding. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 13109/114946 control chromosomes (1/8, 763 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic GNPTAB variant of 1/447, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/databases cite the variant as Benign. Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -

Mucolipidosis type II

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.3

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

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

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