rs1085307069

Variant names:

• chr7-65961018-TG-T
• rs1085307069
• NM_000181.4:c.1834delC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000181.4(GUSB):​c.1834delC​(p.Gln612ArgfsTer28) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GUSB NM_000181.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• Publications: 0 publications found

Genes affected

GUSB (HGNC:4696): (glucuronidase beta) This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]

GUSB Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000181.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUSB	NM_000181.4	MANE Select	c.1834delC	p.Gln612ArgfsTer28	frameshift	Exon 12 of 12	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.1396delC	p.Gln466ArgfsTer28	frameshift	Exon 10 of 10	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.1264delC	p.Gln422ArgfsTer28	frameshift	Exon 11 of 11	NP_001280033.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUSB	ENST00000304895.9	TSL:1 MANE Select	c.1834delC	p.Gln612ArgfsTer28	frameshift	Exon 12 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000864783.1		c.1918delC	p.Gln640ArgfsTer28	frameshift	Exon 12 of 12	ENSP00000534842.1
	GUSB	ENST00000864792.1		c.1864delC	p.Gln622ArgfsTer28	frameshift	Exon 12 of 12	ENSP00000534851.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mucopolysaccharidosis type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

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: rs1085307069; hg19: chr7-65426005;