12-101830713-AGCCGCCGCCGCC-AGCCGCCGCC

Position:

• chr12-101830713-AGCCGCCGCCGCC-AGCCGCCGCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_024312.5(GNPTAB):​c.-41_-39delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,044,528 control chromosomes in the GnomAD database, including 147,324 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30780 hom., cov: 0)
  • Exomes 𝑓: 0.47 (116544 hom.)
• Consequence: GNPTAB NM_024312.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.219

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-101830713-AGCC-A is Benign according to our data. Variant chr12-101830713-AGCC-A is described in ClinVar as [Benign]. Clinvar id is 261693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101830713-AGCC-A is described in Lovd as [Likely_benign]. Variant chr12-101830713-AGCC-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.-41_-39delGGC		5_prime_UTR_variant	1/21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_006719593.4	c.-41_-39delGGC		5_prime_UTR_variant	1/19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.-41_-39delGGC		5_prime_UTR_variant	1/21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000549940.5	c.-41_-39delGGC		5_prime_UTR_variant	1/11	1		ENSP00000449150.1
GNPTAB	ENST00000392919.4	c.-41_-39delGGC		5_prime_UTR_variant	1/3	1		ENSP00000376651.4
GNPTAB	ENST00000549165.1	c.-41_-39delGGC		upstream_gene_variant		1		ENSP00000450413.1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 93676 AN: 149246 Hom.: 30737 Cov.: 0

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.614

GnomAD3 exomes AF: 0.545 AC: 85703 AN: 157184 Hom.: 25726 AF XY: 0.543 AC XY: 47365 AN XY: 87190

Gnomad AFR exome AF: 0.702

Gnomad AMR exome AF: 0.585

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.838

Gnomad SAS exome AF: 0.593

Gnomad FIN exome AF: 0.555

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.471 AC: 421353 AN: 895176 Hom.: 116544 AF XY: 0.478 AC XY: 221553 AN XY: 463766

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.573

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.522

GnomAD4 genome AF: 0.628 AC: 93780 AN: 149352 Hom.: 30780 Cov.: 0 AF XY: 0.630 AC XY: 45819 AN XY: 72740

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.560

Gnomad4 EAS AF: 0.841

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.516

Gnomad4 OTH AF: 0.618

Bravo AF: 0.637

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Mucolipidosis type II Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Pseudo-Hurler polydystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Mucolipidosis, Type III Alpha/Beta Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs76300806; hg19: chr12-102224491;