Genetic Variant NM_024312.5:c.3428dupA (chr12-101757217-G-GT) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_024312.5(GNPTAB):c.3428dupA(p.Asn1143LysfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000043 in 1,396,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 4.77

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 Pathogenic. Variant got 12 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;

PP5

Variant 12-101757217-G-GT is Pathogenic according to our data. Variant chr12-101757217-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 39072.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5 link	c.3428dupA	p.Asn1143LysfsTer3	frameshift_variant	Exon 18 of 21	ENST00000299314.12	NP_077288.2	Q3T906-1
GNPTAB	XM_011538731.3 link	c.3347dupA	p.Asn1116LysfsTer3	frameshift_variant	Exon 18 of 21		XP_011537033.1
GNPTAB	XM_006719593.4 link	c.3428dupA	p.Asn1143LysfsTer3	frameshift_variant	Exon 18 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNPTAB	ENST00000299314.12 link	c.3428dupA	p.Asn1143LysfsTer3	frameshift_variant	Exon 18 of 21	1	NM_024312.5	ENSP00000299314.7	Q3T906-1
GNPTAB	ENST00000550718.1 link	c.239dupA	p.Asn80fs	frameshift_variant	Exon 3 of 4	3		ENSP00000449557.1	H0YIK3
GNPTAB	ENST00000549194.1 link	n.294dupA		non_coding_transcript_exon_variant	Exon 3 of 3	3
GNPTAB	ENST00000549738.5 link	n.179dupA		non_coding_transcript_exon_variant	Exon 2 of 5	4		ENSP00000450161.1	H0YIU2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000430

AC:

AN:

1396862

Hom.:

Cov.:

AF XY:

0.00000429

AC XY:

AN XY:

698644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.49e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II

Pathogenic:1

Nov 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as c.3428_3429insA. This premature translational stop signal has been observed in individual(s) with mucolipidosis II (PMID: 19197337). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1143Lysfs*3) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). ClinVar contains an entry for this variant (Variation ID: 39072). For these reasons, this variant has been classified as Pathogenic. -

Mucolipidosis type II

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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