rs1061361

Positions:

• chr7-65964372-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000181.4(GUSB):​c.1740C>T​(p.Tyr580=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,610,650 control chromosomes in the GnomAD database, including 11,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1084 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10297 hom.)
• Consequence: GUSB NM_000181.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.649

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 7-65964372-G-A is Benign according to our data. Variant chr7-65964372-G-A is described in ClinVar as [Benign]. Clinvar id is 92587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-65964372-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.649 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUSB	NM_000181.4	c.1740C>T	p.Tyr580=	synonymous_variant	11/12	ENST00000304895.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUSB	ENST00000304895.9	c.1740C>T	p.Tyr580=	synonymous_variant	11/12	1	NM_000181.4	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16677 AN: 152052 Hom.: 1083 Cov.: 32

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.132 AC: 33123 AN: 251418 Hom.: 2624 AF XY: 0.134 AC XY: 18205 AN XY: 135894

Gnomad AFR exome AF: 0.0809

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.111 AC: 162161 AN: 1458480 Hom.: 10297 Cov.: 31 AF XY: 0.114 AC XY: 82640 AN XY: 725602

Gnomad4 AFR exome AF: 0.0822

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.0708

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.110 AC: 16682 AN: 152170 Hom.: 1084 Cov.: 32 AF XY: 0.112 AC XY: 8329 AN XY: 74374

Gnomad4 AFR AF: 0.0830

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.0619

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.130

Alfa AF: 0.119 Hom.: 368

Bravo AF: 0.117

Asia WGS AF: 0.149 AC: 523 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2018	Variant summary: GUSB c.1740C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 in silico splicing program predict no significant changes to the splicing site. The variant allele was found at a frequency of 0.13 in 277156 control chromosomes in the gnomAD database, including 2752 homozygotes. The observed variant frequency is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in GUSB causing Mucopolysaccharidosis Type VI (Sly Syndrome) phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1740C>T in individuals affected with Mucopolysaccharidosis Type VI (Sly Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation, and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Mucopolysaccharidosis type 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.28
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs1061361; hg19: chr7-65429359; COSMIC: COSV59223092; COSMIC: COSV59223092;