chr17-42536480-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000263.4(NAGLU):c.208G>C(p.Gly70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,214,376 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G70G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.50

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NAGLU	NM_000263.4 link	c.208G>C	p.Gly70Arg	missense_variant	Exon 1 of 6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2 link	c.208G>C	p.Gly70Arg	missense_variant	Exon 1 of 7		XP_024306539.1
NAGLU	XM_047436138.1 link	c.-254G>C		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.208G>C	p.Gly70Arg	missense_variant	Exon 1 of 6	1	NM_000263.4	ENSP00000225927.1
NAGLU	ENST00000586516.5 link	c.-44G>C		upstream_gene_variant		2		ENSP00000467135.1
NAGLU	ENST00000591587.1 link	c.-50G>C		upstream_gene_variant		5		ENSP00000467836.1
ENSG00000266929	ENST00000585572.1 link	n.-30G>C		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1064384

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

510232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21288

American (AMR)

AF:

0.00

AC:

AN:

7960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13374

East Asian (EAS)

AF:

0.00

AC:

AN:

21400

South Asian (SAS)

AF:

0.00

AC:

AN:

24666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2866

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

911388

Other (OTH)

AF:

0.0000243

AC:

AN:

41198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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

AF:

0.0000133

AC:

AN:

149992

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41204

American (AMR)

AF:

0.00

AC:

AN:

15074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

67168

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NAGLU c.208G>C (p.Gly70Arg) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, N-terminal (IPR024240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 13176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.208G>C has been reported in the literature in an individual affected with Mucopolysaccharidosis (Pollard_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22976768). ClinVar contains an entry for this variant (Variation ID: 557699). Based on the evidence outlined above, the variant was classified as uncertain significance.

Mucopolysaccharidosis, MPS-III-B

Uncertain:1

Apr 10, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.5

PhyloP100

3.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.33

REVEL

Uncertain

0.36

Sift

Benign

0.53

Sift4G

Benign

0.53

Vest4

0.47

ClinPred

0.94

GERP RS

4.4

PromoterAI

0.0044

Neutral

(source)

Varity_R

0.49

gMVP

0.51

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over