Genetic Variant NAGLU:p.Glu120Lys (chr17-42536630-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000263.4(NAGLU):c.358G>A(p.Glu120Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 1,347,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. E120G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.568

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000263.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21242508).

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.358G>A	p.Glu120Lys	missense	Exon 1 of 6	NP_000254.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.358G>A	p.Glu120Lys	missense	Exon 1 of 6	ENSP00000225927.1
NAGLU	ENST00000586516.5	TSL:2	c.107G>A	p.Gly36Glu	missense	Exon 1 of 4	ENSP00000467135.1
NAGLU	ENST00000591587.1	TSL:5	c.101G>A	p.Gly34Glu	missense	Exon 1 of 4	ENSP00000467836.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000371

AC:

AN:

1347404

Hom.:

Cov.:

AF XY:

0.00000301

AC XY:

AN XY:

664274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27568

American (AMR)

AF:

0.00

AC:

AN:

31460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23896

East Asian (EAS)

AF:

0.00

AC:

AN:

31236

South Asian (SAS)

AF:

0.0000397

AC:

AN:

75572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4782

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1063750

Other (OTH)

AF:

0.00

AC:

AN:

56092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.13

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

-0.43

PhyloP100

0.57

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.66

REVEL

Uncertain

0.34

Sift

Benign

0.94

Sift4G

Benign

0.94

Polyphen

0.017

Vest4

0.083

MutPred

0.51

Gain of ubiquitination at E120 (P = 0.0267)

MVP

0.72

MPC

0.42

ClinPred

0.11

GERP RS

1.4

PromoterAI

0.017

Neutral

(source)

Varity_R

0.21

gMVP

0.61

Mutation Taster

=93/7

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over