chr17-80219805-AAGACAGCTGAGACACAGGCTCTGGGGTCGGAAATGAGAGCCAGGAGGGCACCCTGTCTGCAGTCTCTGGGGACCGGAGCACCAGCCCCTCCTCTGGGATCCCCTCCCAAGAGGGATTTGAGATCCGTGGACCCCTGAGCCCTGGCTGGGCAGGGTCAGAGGAGGGTGGGACAGGCGGCACGAGGTAAGTGTAGGGGTGCTGGATGCTGGGGCTCACTCCTCCAGCCTTTGCTGCCCTCTCTGGGGAGACACCCGTGAAGAGTCTGGGGGCGGCACAGAGAGGAGGACGAGAGGGAATGGCAGCGGGGGATACAAGGGCAGGGCACACTAGGGTCAGCATTGACCACGGGTGGGGAGGAGGCCAGTGGCCACTTCCCCGGGCCACCGCAGGTGGGCGTGGGGGGGCGGCGCCGGCACTCACCGAGGAGCAGCAGTGCGTTCCGGGGACGCGCCCGGCAGAGCCCCAGGACTAGC-A

Variant names:

Variant summary

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

The NM_000199.5(SGSH):c.36_88+420del(p.Leu13fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SGSH
NM_000199.5 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.520

Variant links:

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

SGSH links:

SLC26A11 (HGNC:14471): (solute carrier family 26 member 11) This gene encodes a member of the solute linked carrier 26 family of anion exchangers. Members of this family of proteins are essential for numerous cellular functions including homeostasis and intracellular electrolyte balance. The encoded protein is a sodium independent sulfate transporter that is sensitive to the anion exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]

SLC26A11 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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 46 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-80219805-AAGACAGCTGAGACACAGGCTCTGGGGTCGGAAATGAGAGCCAGGAGGGCACCCTGTCTGCAGTCTCTGGGGACCGGAGCACCAGCCCCTCCTCTGGGATCCCCTCCCAAGAGGGATTTGAGATCCGTGGACCCCTGAGCCCTGGCTGGGCAGGGTCAGAGGAGGGTGGGACAGGCGGCACGAGGTAAGTGTAGGGGTGCTGGATGCTGGGGCTCACTCCTCCAGCCTTTGCTGCCCTCTCTGGGGAGACACCCGTGAAGAGTCTGGGGGCGGCACAGAGAGGAGGACGAGAGGGAATGGCAGCGGGGGATACAAGGGCAGGGCACACTAGGGTCAGCATTGACCACGGGTGGGGAGGAGGCCAGTGGCCACTTCCCCGGGCCACCGCAGGTGGGCGTGGGGGGGCGGCGCCGGCACTCACCGAGGAGCAGCAGTGCGTTCCGGGGACGCGCCCGGCAGAGCCCCAGGACTAGC-A is Pathogenic according to our data. Variant chr17-80219805-AAGACAGCTGAGACACAGGCTCTGGGGTCGGAAATGAGAGCCAGGAGGGCACCCTGTCTGCAGTCTCTGGGGACCGGAGCACCAGCCCCTCCTCTGGGATCCCCTCCCAAGAGGGATTTGAGATCCGTGGACCCCTGAGCCCTGGCTGGGCAGGGTCAGAGGAGGGTGGGACAGGCGGCACGAGGTAAGTGTAGGGGTGCTGGATGCTGGGGCTCACTCCTCCAGCCTTTGCTGCCCTCTCTGGGGAGACACCCGTGAAGAGTCTGGGGGCGGCACAGAGAGGAGGACGAGAGGGAATGGCAGCGGGGGATACAAGGGCAGGGCACACTAGGGTCAGCATTGACCACGGGTGGGGAGGAGGCCAGTGGCCACTTCCCCGGGCCACCGCAGGTGGGCGTGGGGGGGCGGCGCCGGCACTCACCGAGGAGCAGCAGTGCGTTCCGGGGACGCGCCCGGCAGAGCCCCAGGACTAGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2028484.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5 link	c.36_88+420del	p.Leu13fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 8	ENST00000326317.11	NP_000190.1	P51688
SLC26A11	NM_001166347.2 link	c.-904_-432del		upstream_gene_variant		ENST00000361193.8	NP_001159819.1	Q86WA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 link	c.36_88+420del	p.Leu13fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 8	1	NM_000199.5	ENSP00000314606.6		P51688
SLC26A11	ENST00000361193.8 link	c.-904_-432del		upstream_gene_variant		1	NM_001166347.2	ENSP00000355384.3		Q86WA9

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals affected with SGSH-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 1 (c.36_88+420del) of the SGSH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SGSH are known to be pathogenic (PMID: 11182930, 21204211, 22976768). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

No publications associated with this variant yet.