NM_000181.4:c.1740C>A

Variant names:

• chr7-65964372-G-T
• rs1061361
• NM_000181.4:c.1740C>A

Variant summary

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

The NM_000181.4(GUSB):​c.1740C>A​(p.Tyr580*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y580Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUSB NM_000181.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.649
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 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.1740C>A	p.Tyr580*	stop_gained	Exon 11 of 12	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.1302C>A	p.Tyr434*	stop_gained	Exon 9 of 10	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.1170C>A	p.Tyr390*	stop_gained	Exon 10 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.1740C>A	p.Tyr580*	stop_gained	Exon 11 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000461622.1	TSL:1	n.265C>A		non_coding_transcript_exon	Exon 2 of 2
	GUSB	ENST00000864783.1		c.1824C>A	p.Tyr608*	stop_gained	Exon 11 of 12	ENSP00000534842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.45	N
PhyloP100		-0.65
Vest4		0.99
GERP RS		-1.4
Mutation Taster		=9/191	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1061361; hg19: chr7-65429359; COSMIC: COSV105177068; COSMIC: COSV105177068;