rs79493678

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024312.5(GNPTAB):c.3602+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,608,380 control chromosomes in the GnomAD database, including 1,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 90 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1322 hom. )

Consequence

GNPTAB
NM_024312.5 splice_region, intron

Scores

Splicing: ADA: 0.0003069

Clinical Significance

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

Conservation

PhyloP100: -0.346

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-101753364-G-T is Benign according to our data. Variant chr12-101753364-G-T is described in ClinVar as [Benign]. Clinvar id is 96122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101753364-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0288 (4375/151848) while in subpopulation NFE AF= 0.0461 (3136/68000). AF 95% confidence interval is 0.0448. There are 90 homozygotes in gnomad4. There are 2068 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 90 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5 linkuse as main transcript	c.3602+8C>A		splice_region_variant, intron_variant		ENST00000299314.12
GNPTAB	XM_011538731.3 linkuse as main transcript	c.3521+8C>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12 linkuse as main transcript	c.3602+8C>A		splice_region_variant, intron_variant		1	NM_024312.5	P1	Q3T906-1
GNPTAB	ENST00000549738.5 linkuse as main transcript	c.*209+8C>A		splice_region_variant, intron_variant, NMD_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0289

AC:

4378

AN:

151728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00652

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0448

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0461

Gnomad OTH

AF:

0.0277

GnomAD3 exomes

AF:

0.0325

AC:

8157

AN:

251282

Hom.:

202

AF XY:

0.0327

AC XY:

4437

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00674

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0258

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00506

Gnomad FIN exome

AF:

0.0491

Gnomad NFE exome

AF:

0.0502

Gnomad OTH exome

AF:

0.0368

GnomAD4 exome

AF:

0.0392

AC:

57109

AN:

1456532

Hom.:

1322

Cov.:

AF XY:

0.0384

AC XY:

27853

AN XY:

724966

show subpopulations

Gnomad4 AFR exome

AF:

0.00579

Gnomad4 AMR exome

AF:

0.0177

Gnomad4 ASJ exome

AF:

0.0271

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00547

Gnomad4 FIN exome

AF:

0.0493

Gnomad4 NFE exome

AF:

0.0454

Gnomad4 OTH exome

AF:

0.0311

GnomAD4 genome

AF:

0.0288

AC:

4375

AN:

151848

Hom.:

Cov.:

AF XY:

0.0279

AC XY:

2068

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00648

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0448

Gnomad4 NFE

AF:

0.0461

Gnomad4 OTH

AF:

0.0274

Alfa

AF:

0.0391

Hom.:

Bravo

AF:

0.0261

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0420

EpiControl

AF:

0.0438

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2019	Variant summary: GNPTAB c.3602+8C>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.032 in 251282 control chromosomes in the gnomAD database, including 202 homozygotes. The observed variant frequency is approximately 14.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in GNPTAB causing Mucolipidosis phenotype (0.0022), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3602+8C>A in individuals affected with Mucolipidosis and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions (evaluation after 2014) cite the variant three times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Mucolipidosis type II

Benign:3

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 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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 12, 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;C2673377:Mucolipidosis type II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

0.44

Dann

Benign

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00031

dbscSNV1_RF

Benign

0.054

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

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