12-101757576-AT-A

Variant names:

• chr12-101757576-AT-A
• rs281865014
• NM_024312.5:c.3330delA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_024312.5(GNPTAB):​c.3330delA​(p.Lys1110AsnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,309,074 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.3330delA	p.Lys1110AsnfsTer16	frameshift_variant	Exon 17 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.3249delA	p.Lys1083AsnfsTer16	frameshift_variant	Exon 17 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.3330delA	p.Lys1110AsnfsTer16	frameshift_variant	Exon 17 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3330delA	p.Lys1110AsnfsTer16	frameshift_variant	Exon 17 of 21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000550718.1	c.141delA	p.Lys47fs	frameshift_variant	Exon 2 of 4	3		ENSP00000449557.1
GNPTAB	ENST00000549194.1	n.196delA		non_coding_transcript_exon_variant	Exon 2 of 3	3
GNPTAB	ENST00000549738.5	n.81delA		non_coding_transcript_exon_variant	Exon 1 of 5	4		ENSP00000450161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1309074 Hom.: 0 Cov.: 21 AF XY: 0.00000152 AC XY: 1 AN XY: 659530

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30422

American (AMR) AF: 0.00 AC: 0 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 38860

South Asian (SAS) AF: 0.00 AC: 0 AN: 83130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 972932

Other (OTH) AF: 0.00 AC: 0 AN: 55418

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53

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: rs281865014; hg19: chr12-102151354;