rs377519272

Variant names:

• chr7-65967767-G-A
• rs377519272
• NM_000181.4:c.1617C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-65967767-G-A
• chr7-65967767-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000181.4(GUSB):​c.1617C>T​(p.Ser539Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002243058: Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID:7633414, 30442200)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: GUSB NM_000181.4 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.780
• Publications: 8 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002243058: Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 7633414, 30442200).; SCV002768930: "Functional studies in fibroblasts found variant protein had significantly reduced enzyme activity compared to wild type protein (PMID: 7633414)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-65967767-G-A is Pathogenic according to our data. Variant chr7-65967767-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1617C>T	p.Ser539Ser	synonymous	Exon 10 of 12	NP_000172.2	P08236-1
	GUSB	NM_001284290.2		c.1179C>T	p.Ser393Ser	synonymous	Exon 8 of 10	NP_001271219.1	P08236-3
	GUSB	NM_001293104.2		c.1047C>T	p.Ser349Ser	synonymous	Exon 9 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.1617C>T	p.Ser539Ser	synonymous	Exon 10 of 12	ENSP00000302728.4	P08236-1
	GUSB	ENST00000461622.1	TSL:1	n.142C>T		non_coding_transcript_exon	Exon 1 of 2
	GUSB	ENST00000864783.1		c.1701C>T	p.Ser567Ser	synonymous	Exon 10 of 12	ENSP00000534842.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251100 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000760 AC: 111 AN: 1461242 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000971 AC: 108 AN: 1111826

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Mucopolysaccharidosis type 7 (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Benign	0.57
PhyloP100		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: 2

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

Other links and lift over

dbSNP: rs377519272; hg19: chr7-65432754;