7-65960907-A-G

Variant names:

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. 16/22 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

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 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 id is 92588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-65960907-A-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUSB	NM_000181.4 link	c.1946T>C	p.Leu649Pro	missense_variant	Exon 12 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.1946T>C	p.Leu649Pro	missense_variant	Exon 12 of 12	1	NM_000181.4	ENSP00000302728.4		P08236-1

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

Gnomad4 AFR exome

AF:

0.355

AC:

11865

AN:

33456

Gnomad4 AMR exome

AF:

0.550

AC:

24615

AN:

44720

Gnomad4 ASJ exome

AF:

0.642

AC:

16788

AN:

26130

Gnomad4 EAS exome

AF:

0.880

AC:

34917

AN:

39694

Gnomad4 SAS exome

AF:

0.636

AC:

54836

AN:

86244

Gnomad4 FIN exome

AF:

0.621

AC:

33185

AN:

53396

Gnomad4 NFE exome

AF:

0.553

AC:

613983

AN:

1110826

Gnomad4 Remaining exome

AF:

0.570

AC:

34395

AN:

60338

Heterozygous variant carriers

18716

37431

56147

74862

93578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.367

AC:

0.366978

AN:

0.366978

Gnomad4 AMR

AF:

0.529

AC:

0.529462

AN:

0.529462

Gnomad4 ASJ

AF:

0.632

AC:

0.631503

AN:

0.631503

Gnomad4 EAS

AF:

0.837

AC:

0.837354

AN:

0.837354

Gnomad4 SAS

AF:

0.655

AC:

0.655287

AN:

0.655287

Gnomad4 FIN

AF:

0.612

AC:

0.611543

AN:

0.611543

Gnomad4 NFE

AF:

0.552

AC:

0.551897

AN:

0.551897

Gnomad4 OTH

AF:

0.531

AC:

0.531309

AN:

0.531309

Heterozygous variant carriers

1799

3598

5396

7195

8994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 14, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 58% of total chromosomes in ExAC -

Apr 16, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GUSB c.1946T>C (p.Leu649Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.58 in 276996 control chromosomes, suggesting that it is the major allele and therefore benign. To our knowledge, no occurrence of c.1946T>C in individuals affected with Mucopolysaccharidosis Type VI (Sly Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Mucopolysaccharidosis type 7

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

5.4

DANN

Benign

0.50

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.24

Sift

Benign

0.71

T;T

Sift4G

Benign

0.097

T;T

Polyphen

0.0

B;.

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)

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over