chr12-64729017-T-TAGGAC

Position:

• chr12-64729017-T-TAGGAC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002076.4(GNS):​c.1138_1139insGTCCT​(p.Asp380GlyfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNS NM_002076.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

Genes affected

GNS (HGNC:4422): (glucosamine (N-acetyl)-6-sulfatase) The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 12-64729017-T-TAGGAC is Pathogenic according to our data. Variant chr12-64729017-T-TAGGAC is described in ClinVar as [Pathogenic]. Clinvar id is 2935.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNS	NM_002076.4	c.1138_1139insGTCCT	p.Asp380GlyfsTer9	frameshift_variant	10/14	ENST00000258145.8	NP_002067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNS	ENST00000258145.8	c.1138_1139insGTCCT	p.Asp380GlyfsTer9	frameshift_variant	10/14	1	NM_002076.4	ENSP00000258145	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-D Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs483352899; hg19: chr12-65122797;