rs104894599

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1_Very_StrongPM1PP3_StrongPP5_Moderate

The NM_000263.4(NAGLU):c.144C>A(p.Phe48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,098,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F48F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.253

Publications

5 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: Pathogenic. The variant received 16 ACMG points.

PS1

Transcript NM_000263.4 (NAGLU) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a strand (size 4) in uniprot entity ANAG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000263.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 17-42536416-C-A is Pathogenic according to our data. Variant chr17-42536416-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2138021.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NAGLU	NM_000263.4 link	c.144C>A	p.Phe48Leu	missense_variant	Exon 1 of 6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2 link	c.144C>A	p.Phe48Leu	missense_variant	Exon 1 of 7		XP_024306539.1
NAGLU	XM_047436138.1 link	c.-318C>A		5_prime_UTR_variant	Exon 1 of 5		XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NAGLU	ENST00000225927.7 link	c.144C>A	p.Phe48Leu	missense_variant	Exon 1 of 6	1	NM_000263.4	ENSP00000225927.1
NAGLU	ENST00000586516.5 link	c.-108C>A		upstream_gene_variant		2		ENSP00000467135.1
NAGLU	ENST00000591587.1 link	c.-114C>A		upstream_gene_variant		5		ENSP00000467836.1
ENSG00000266929	ENST00000585572.1 link	n.-94C>A		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1098134

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

531702

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22160

American (AMR)

AF:

0.00

AC:

AN:

17018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16432

East Asian (EAS)

AF:

0.00

AC:

AN:

19570

South Asian (SAS)

AF:

0.0000269

AC:

AN:

37228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2938

European-Non Finnish (NFE)

AF:

0.0000348

AC:

AN:

919456

Other (OTH)

AF:

0.00

AC:

AN:

42054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Mar 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies have shown that this missense change affects NAGLU function (PMID: 11068184). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function. This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 10094189). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 48 of the NAGLU protein (p.Phe48Leu). This variant disrupts the p.Phe48 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9832037, 29979746). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Benign

0.042

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.8

PhyloP100

0.25

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.73

Sift

Benign

0.034

Sift4G

Benign

0.10

Polyphen

0.98

Vest4

0.74

MutPred

0.86

Gain of disorder (P = 0.0662);

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

3.4

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.82

gMVP

0.76

Mutation Taster

=30/70

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over