rs121918175

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000181.4(GUSB):c.1061C>T(p.Ala354Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A354A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GUSB
NM_000181.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 4.53

Publications

7 publications found

Variant links:

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: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

GUSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000181.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 7-65974923-G-A is Pathogenic according to our data. Variant chr7-65974923-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 896.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUSB	NM_000181.4 link	c.1061C>T	p.Ala354Val	missense_variant	Exon 6 of 12	ENST00000304895.9	NP_000172.2	P08236-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUSB	ENST00000304895.9 link	c.1061C>T	p.Ala354Val	missense_variant	Exon 6 of 12	1	NM_000181.4	ENSP00000302728.4		P08236-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251142

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461326

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111702

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000330

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 7

Pathogenic:1Uncertain:1

Apr 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the GUSB protein (p.Ala354Val). This variant is present in population databases (rs121918175, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VII (PMID: 8111413). ClinVar contains an entry for this variant (Variation ID: 896). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GUSB function (PMID: 8111413). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jan 04, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on residual enzymatic activity (PMID: 8111413).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19224584, 8111413, 6811712) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

4.5

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.7

D;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.99

D;.

Vest4

0.81

MutPred

0.86

Loss of ubiquitination at K350 (P = 0.0648);.;

MVP

0.97

MPC

1.1

ClinPred

0.93

GERP RS

5.1

Varity_R

0.53

gMVP

0.81

Mutation Taster

=23/77

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over