rs1329159364

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The ENST00000225927.7(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
ENST00000225927.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000225927.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NAGLU	NM_000263.4 linkuse as main transcript	c.208G>C	p.Gly70Arg	missense_variant	1/6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2 linkuse as main transcript	c.208G>C	p.Gly70Arg	missense_variant	1/7		XP_024306539.1
NAGLU	XM_047436138.1 linkuse as main transcript	c.-254G>C		5_prime_UTR_variant	1/5		XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NAGLU	ENST00000225927.7 linkuse as main transcript	c.208G>C	p.Gly70Arg	missense_variant	1/6	1	NM_000263.4	ENSP00000225927	P1
NAGLU	ENST00000586516.5 linkuse as main transcript			upstream_gene_variant		2		ENSP00000467135
NAGLU	ENST00000591587.1 linkuse as main transcript			upstream_gene_variant		5		ENSP00000467836

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000143

Gnomad4 OTH exome

AF:

0.0000243

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149992

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73144

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000298

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 16, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 10, 2018

- -

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

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

MutationTaster

Benign

0.88

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.33

REVEL

Uncertain

0.36

Sift

Benign

0.53

Sift4G

Benign

0.53

Polyphen

0.99

Vest4

0.47

MutPred

0.59

Gain of methylation at G70 (P = 0.0026);

MVP

0.95

MPC

1.1

ClinPred

0.94

GERP RS

4.4

Varity_R

0.49

gMVP

0.51

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