7-65964382-C-T

Variant names:

• chr7-65964382-C-T
• rs121918183
• NM_000181.4:c.1730G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000181.4(GUSB):​c.1730G>A​(p.Arg577His) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R577C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GUSB NM_000181.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-65964382-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 902.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

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.1730G>A	p.Arg577His	missense	Exon 11 of 12	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.1292G>A	p.Arg431His	missense	Exon 9 of 10	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.1160G>A	p.Arg387His	missense	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.1730G>A	p.Arg577His	missense	Exon 11 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000461622.1	TSL:1	n.255G>A		non_coding_transcript_exon	Exon 2 of 2
	GUSB	ENST00000864783.1		c.1814G>A	p.Arg605His	missense	Exon 11 of 12	ENSP00000534842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458980 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725860

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4142

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111140

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.77		Loss of MoRF binding (P = 0.0708)
MVP		0.98
MPC		0.75
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.80
Mutation Taster		=24/76	disease causing

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: rs121918183; hg19: chr7-65429369;