rs86312

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_StrongBS1BS2

The NM_000263.4(NAGLU):c.2209C>A(p.Arg737Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,610,882 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R737G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 31)

Exomes 𝑓: 0.020 ( 341 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.635

Publications

47 publications found

Variant links:

Genes affected

NAGLU (HGNC:7632): (N-acetyl-alpha-glucosaminidase) This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. [provided by RefSeq, Jul 2008]

NAGLU Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 3B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health
Charcot-Marie-Tooth disease axonal type 2V
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

NAGLU links:

ENSG00000266929 (HGNC:):

ENSG00000266929 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=0.0029644072).

BP6

Variant 17-42544215-C-A is Benign according to our data. Variant chr17-42544215-C-A is described in ClinVar as Benign. ClinVar VariationId is 92692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0146 (2220/152118) while in subpopulation SAS AF = 0.0309 (149/4824). AF 95% confidence interval is 0.0268. There are 26 homozygotes in GnomAd4. There are 1135 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	NM_000263.4	MANE Select	c.2209C>A	p.Arg737Ser	missense	Exon 6 of 6	NP_000254.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.2209C>A	p.Arg737Ser	missense	Exon 6 of 6	ENSP00000225927.1
ENSG00000266929	ENST00000585572.1	TSL:4	n.379+5460C>A		intron	N/A
NAGLU	ENST00000591587.1	TSL:5	c.*1178C>A		downstream_gene	N/A	ENSP00000467836.1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2221

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0309

Gnomad FIN

AF:

0.0269

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0184

AC:

4553

AN:

247800

AF XY:

0.0198

show subpopulations

Gnomad AFR exome

AF:

0.00361

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.00697

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0182

GnomAD4 exome

AF:

0.0197

AC:

28690

AN:

1458764

Hom.:

341

Cov.:

AF XY:

0.0202

AC XY:

14625

AN XY:

725758

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33480

American (AMR)

AF:

0.00599

AC:

268

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00738

AC:

193

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0348

AC:

3001

AN:

86256

European-Finnish (FIN)

AF:

0.0252

AC:

1268

AN:

50332

Middle Eastern (MID)

AF:

0.0121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0205

AC:

22827

AN:

1111990

Other (OTH)

AF:

0.0161

AC:

975

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1908

3816

5724

7632

9540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.0146

AC:

2220

AN:

152118

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1135

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00357

AC:

148

AN:

41460

American (AMR)

AF:

0.00759

AC:

116

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.0309

AC:

149

AN:

4824

European-Finnish (FIN)

AF:

0.0269

AC:

284

AN:

10576

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0210

AC:

1430

AN:

68020

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

110

219

329

438

548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0108

Hom.:

6616

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0195

AC:

ExAC

AF:

0.0192

AC:

2325

EpiCase

AF:

0.0192

EpiControl

AF:

0.0201

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Mucopolysaccharidosis, MPS-III-B (3)

Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.088

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0030

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.9

PhyloP100

0.64

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.19

REVEL

Uncertain

0.37

Sift

Benign

0.049

Sift4G

Benign

0.081

Polyphen

0.47

Vest4

0.089

MPC

0.47

ClinPred

0.021

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.26

Mutation Taster

=92/8

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over