rs9530

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000181.4(GUSB):c.1946T>C(p.Leu649Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,612,328 control chromosomes in the GnomAD database, including 260,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L649L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.52 ( 21363 hom., cov: 30)

Exomes 𝑓: 0.57 ( 239008 hom. )

Consequence

GUSB
NM_000181.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

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

GUSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0806422E-6).

BP6

Variant 7-65960907-A-G is Benign according to our data. Variant chr7-65960907-A-G is described in ClinVar as Benign. ClinVar VariationId is 92588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

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	UniProt
GUSB	NM_000181.4	MANE Select	c.1946T>C	p.Leu649Pro	missense	Exon 12 of 12	NP_000172.2	P08236-1
GUSB	NM_001284290.2		c.1508T>C	p.Leu503Pro	missense	Exon 10 of 10	NP_001271219.1	P08236-3
GUSB	NM_001293104.2		c.1376T>C	p.Leu459Pro	missense	Exon 11 of 11	NP_001280033.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GUSB	ENST00000304895.9	TSL:1 MANE Select	c.1946T>C	p.Leu649Pro	missense	Exon 12 of 12	ENSP00000302728.4	P08236-1
GUSB	ENST00000864783.1		c.2030T>C	p.Leu677Pro	missense	Exon 12 of 12	ENSP00000534842.1
GUSB	ENST00000864792.1		c.1976T>C	p.Leu659Pro	missense	Exon 12 of 12	ENSP00000534851.1

Frequencies

GnomAD3 genomes

AF:

0.519

AC:

78643

AN:

151644

Hom.:

21348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.367

Gnomad AMI

AF:

0.626

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.632

Gnomad EAS

AF:

0.837

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.612

Gnomad MID

AF:

0.669

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.528

GnomAD2 exomes

AF:

0.585

AC:

147110

AN:

251348

AF XY:

0.590

show subpopulations

Gnomad AFR exome

AF:

0.359

Gnomad AMR exome

AF:

0.556

Gnomad ASJ exome

AF:

0.646

Gnomad EAS exome

AF:

0.836

Gnomad FIN exome

AF:

0.624

Gnomad NFE exome

AF:

0.558

Gnomad OTH exome

AF:

0.586

GnomAD4 exome

AF:

0.567

AC:

828239

AN:

1460566

Hom.:

239008

Cov.:

AF XY:

0.571

AC XY:

414733

AN XY:

726652

show subpopulations

African (AFR)

AF:

0.355

AC:

11865

AN:

33456

American (AMR)

AF:

0.550

AC:

24615

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.642

AC:

16788

AN:

26130

East Asian (EAS)

AF:

0.880

AC:

34917

AN:

39694

South Asian (SAS)

AF:

0.636

AC:

54836

AN:

86244

European-Finnish (FIN)

AF:

0.621

AC:

33185

AN:

53396

Middle Eastern (MID)

AF:

0.634

AC:

3655

AN:

5762

European-Non Finnish (NFE)

AF:

0.553

AC:

613983

AN:

1110826

Other (OTH)

AF:

0.570

AC:

34395

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

18716

37431

56147

74862

93578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17322

34644

51966

69288

86610

<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

AF:

0.519

AC:

78690

AN:

151762

Hom.:

21363

Cov.:

AF XY:

0.524

AC XY:

38859

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.367

AC:

15187

AN:

41384

American (AMR)

AF:

0.529

AC:

8051

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.632

AC:

2185

AN:

3460

East Asian (EAS)

AF:

0.837

AC:

4304

AN:

5140

South Asian (SAS)

AF:

0.655

AC:

3148

AN:

4804

European-Finnish (FIN)

AF:

0.612

AC:

6453

AN:

10552

Middle Eastern (MID)

AF:

0.668

AC:

195

AN:

292

European-Non Finnish (NFE)

AF:

0.552

AC:

37476

AN:

67904

Other (OTH)

AF:

0.531

AC:

1120

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1799

3598

5396

7195

8994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.554

Hom.:

110465

Bravo

AF:

0.507

TwinsUK

AF:

0.553

AC:

2049

ALSPAC

AF:

0.552

AC:

2126

ESP6500AA

AF:

0.369

AC:

1628

ESP6500EA

AF:

0.553

AC:

4756

ExAC

AF:

0.580

AC:

70366

Asia WGS

AF:

0.717

AC:

2495

AN:

3478

EpiCase

AF:

0.560

EpiControl

AF:

0.559

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Mucopolysaccharidosis type 7 (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

5.4

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

PhyloP100

-0.23

PrimateAI

Benign

0.26

PROVEAN

Benign

1.3

REVEL

Benign

0.24

Sift

Benign

0.71

Sift4G

Benign

0.097

Polyphen

0.0

Vest4

0.029

MPC

0.64

ClinPred

0.0069

GERP RS

-0.066

Varity_R

0.045

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over