dbSNP rs544927524: GUSB:p.Leu649Gln (chr7-65960907-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000181.4(GUSB):c.1946T>A(p.Leu649Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L649P) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GUSB
NM_000181.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.232

Publications

69 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13977483).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000181.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GUSB	NM_000181.4	MANE Select	c.1946T>A	p.Leu649Gln	missense	Exon 12 of 12	NP_000172.2
GUSB	NM_001284290.2		c.1508T>A	p.Leu503Gln	missense	Exon 10 of 10	NP_001271219.1
GUSB	NM_001293104.2		c.1376T>A	p.Leu459Gln	missense	Exon 11 of 11	NP_001280033.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GUSB	ENST00000304895.9	TSL:1 MANE Select	c.1946T>A	p.Leu649Gln	missense	Exon 12 of 12	ENSP00000302728.4
GUSB	ENST00000421103.5	TSL:2	c.1508T>A	p.Leu503Gln	missense	Exon 10 of 10	ENSP00000391390.1
GUSB	ENST00000430730.5	TSL:5	n.*1213T>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000411859.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727058

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111676

Other (OTH)

AF:

0.00

AC:

AN:

60378

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.0034

BayesDel_noAF

Benign

-0.24

CADD

Benign

6.0

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.13

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

-0.34

PhyloP100

-0.23

PrimateAI

Benign

0.25

PROVEAN

Benign

0.17

REVEL

Benign

0.27

Sift

Benign

0.059

Sift4G

Benign

0.068

Polyphen

0.16

Vest4

0.17

MutPred

0.22

Loss of stability (P = 0.0037)

MVP

0.84

MPC

0.45

ClinPred

0.13

GERP RS

-0.066

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.063

gMVP

0.33

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over