7-65960725-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000181.4(GUSB):c.*172A>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 0.0282 in 648,770 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (73 hom., cov: 32)
  • Exomes 𝑓: 0.030 (288 hom.)
• Consequence: GUSB NM_000181.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.43

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-65960725-T-C is Benign according to our data. Variant chr7-65960725-T-C is described in ClinVar as [Benign]. Clinvar id is 910523.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0236 (3594/152246) while in subpopulation NFE AF= 0.0365 (2482/68000). AF 95% confidence interval is 0.0353. There are 73 homozygotes in gnomad4. There are 1685 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUSB	NM_000181.4	c.*172A>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.*172A>G		3_prime_UTR_variant	12/12	1	NM_000181.4	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3597 AN: 152128 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00576

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0307

GnomAD4 exome AF: 0.0296 AC: 14702 AN: 496524 Hom.: 288 Cov.: 5 AF XY: 0.0293 AC XY: 7803 AN XY: 266342

Gnomad4 AFR exome AF: 0.00653

Gnomad4 AMR exome AF: 0.0211

Gnomad4 ASJ exome AF: 0.0643

Gnomad4 EAS exome AF: 0.0000310

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0320

GnomAD4 genome AF: 0.0236 AC: 3594 AN: 152246 Hom.: 73 Cov.: 32 AF XY: 0.0226 AC XY: 1685 AN XY: 74432

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0623

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0202 Hom.: 14

Bravo AF: 0.0236

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 7 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.16
Dann	Benign	0.50

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: rs77293332; hg19: chr7-65425712;