rs140016611

chr7-65980398-G-Achr7-65980398-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000181.4(GUSB):c.222C>T(p.Thr74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,162 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T74T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: GUSB NM_000181.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.143

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-65980398-G-A is Benign according to our data. Variant chr7-65980398-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 528234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-65980398-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.143 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00179 (272/152332) while in subpopulation NFE AF= 0.00285 (194/68030). AF 95% confidence interval is 0.00252. There are 0 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUSB	NM_000181.4	c.222C>T	p.Thr74=	synonymous_variant	2/12	ENST00000304895.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUSB	ENST00000304895.9	c.222C>T	p.Thr74=	synonymous_variant	2/12	1	NM_000181.4	P1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00197 AC: 490 AN: 248160 Hom.: 1 AF XY: 0.00205 AC XY: 275 AN XY: 134430

Gnomad AFR exome AF: 0.000946

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00284

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00229 AC: 3338 AN: 1460830 Hom.: 11 Cov.: 34 AF XY: 0.00224 AC XY: 1625 AN XY: 726612

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.00268

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74490

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00164

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00321

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

GUSB-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

GUSB: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.7
Dann	Uncertain	0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs140016611; hg19: chr7-65445385; COSMIC: COSV59221894; COSMIC: COSV59221894;