7-65960689-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000181.4(GUSB):c.*208T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 585,334 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: GUSB NM_000181.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.176

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000394 (60/152350) while in subpopulation SAS AF= 0.00124 (6/4832). AF 95% confidence interval is 0.000541. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUSB	NM_000181.4	c.*208T>G		3_prime_UTR_variant	12/12	ENST00000304895.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUSB	ENST00000304895.9	c.*208T>G		3_prime_UTR_variant	12/12	1	NM_000181.4	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000702 AC: 304 AN: 432984 Hom.: 3 Cov.: 3 AF XY: 0.000809 AC XY: 186 AN XY: 230012

Gnomad4 AFR exome AF: 0.000164

Gnomad4 AMR exome AF: 0.0000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00235

Gnomad4 NFE exome AF: 0.000580

Gnomad4 OTH exome AF: 0.000320

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000268

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 7 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.41
Dann	Benign	0.73

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: rs190201470; hg19: chr7-65425676;