chr12-101830713-AGCC-A

Variant names:

• chr12-101830713-AGCC-A
• rs76300806
• NM_024312.5:c.-41_-39delGGC

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024312.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	NM_024312.5	MANE Select	c.-41_-39delGGC		5_prime_UTR	Exon 1 of 21	NP_077288.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTAB	ENST00000299314.12	TSL:1 MANE Select	c.-41_-39delGGC		5_prime_UTR	Exon 1 of 21	ENSP00000299314.7
	GNPTAB	ENST00000549940.5	TSL:1	c.-41_-39delGGC		5_prime_UTR	Exon 1 of 11	ENSP00000449150.1
	GNPTAB	ENST00000392919.4	TSL:1	c.-41_-39delGGC		5_prime_UTR	Exon 1 of 3	ENSP00000376651.4

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

GnomAD2 exomes AF: 0.545 AC: 85703 AN: 157184 AF XY: 0.543

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 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

African (AFR) AF: 0.783 AC: 13847 AN: 17678

American (AMR) AF: 0.573 AC: 20125 AN: 35098

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 11058 AN: 20868

East Asian (EAS) AF: 0.838 AC: 25408 AN: 30320

South Asian (SAS) AF: 0.583 AC: 40144 AN: 68820

European-Finnish (FIN) AF: 0.568 AC: 26663 AN: 46914

Middle Eastern (MID) AF: 0.551 AC: 1703 AN: 3088

European-Non Finnish (NFE) AF: 0.414 AC: 261629 AN: 632604

Other (OTH) AF: 0.522 AC: 20776 AN: 39786

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

African (AFR) AF: 0.815 AC: 33492 AN: 41088

American (AMR) AF: 0.577 AC: 8713 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1904 AN: 3400

East Asian (EAS) AF: 0.841 AC: 4213 AN: 5012

South Asian (SAS) AF: 0.632 AC: 3024 AN: 4786

European-Finnish (FIN) AF: 0.594 AC: 5997 AN: 10098

Middle Eastern (MID) AF: 0.583 AC: 169 AN: 290

European-Non Finnish (NFE) AF: 0.516 AC: 34361 AN: 66612

Other (OTH) AF: 0.618 AC: 1281 AN: 2074

Alfa AF: 0.470 Hom.: 2213

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Pseudo-Hurler polydystrophy Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucolipidosis type II Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=296/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76300806; hg19: chr12-102224491; COSMIC: COSV54778198; COSMIC: COSV54778198;