Genetic Variant GUSB:p.Asn54Lys (chr7-65982022-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000181.4(GUSB):c.162C>A(p.Asn54Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N54N) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GUSB
NM_000181.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.921

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3700773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUSB	NM_000181.4 link	c.162C>A	p.Asn54Lys	missense_variant	Exon 1 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.162C>A	p.Asn54Lys	missense_variant	Exon 1 of 12	1	NM_000181.4	ENSP00000302728.4		P08236-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458114

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33242

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

86040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4968

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111408

Other (OTH)

AF:

0.0000166

AC:

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

0.046

MutationAssessor

Benign

1.8

L;L

PhyloP100

0.92

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.20

Sift

Benign

0.13

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.24

B;.

Vest4

0.28

MutPred

0.50

Gain of ubiquitination at N54 (P = 0.0211);Gain of ubiquitination at N54 (P = 0.0211);

MVP

0.90

MPC

0.53

ClinPred

0.21

GERP RS

1.6

PromoterAI

0.094

Neutral

(source)

Varity_R

0.24

gMVP

0.67

Mutation Taster

=51/49

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over