rs61737294

Positions:

chr17-42537435-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000263.4(NAGLU):c.421T>A(p.Ser141Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,614,212 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S141S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.019 ( 103 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 74 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.63

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:

ENSG00000266929 (HGNC:):

ENSG00000266929 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009859383).

BP6

Variant 17-42537435-T-A is Benign according to our data. Variant chr17-42537435-T-A is described in ClinVar as [Benign]. Clinvar id is 235755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42537435-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4 linkuse as main transcript	c.421T>A	p.Ser141Thr	missense_variant	2/6	ENST00000225927.7	NP_000254.2	P54802A0A140VJE4
NAGLU	XM_024450771.2 linkuse as main transcript	c.478T>A	p.Ser160Thr	missense_variant	3/7		XP_024306539.1
NAGLU	XM_047436138.1 linkuse as main transcript	c.-79+780T>A		intron_variant			XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7 linkuse as main transcript	c.421T>A	p.Ser141Thr	missense_variant	2/6	1	NM_000263.4	ENSP00000225927.1		P54802

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2964

AN:

152220

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0681

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00706

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00510

AC:

1282

AN:

251452

Hom.:

AF XY:

0.00389

AC XY:

529

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0712

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00178

AC:

2601

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1125

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0637

Gnomad4 AMR exome

AF:

0.00353

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00404

GnomAD4 genome

AF:

0.0195

AC:

2966

AN:

152338

Hom.:

103

Cov.:

AF XY:

0.0189

AC XY:

1405

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0679

Gnomad4 AMR

AF:

0.00705

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00289

Hom.:

Bravo

AF:

0.0217

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0733

AC:

323

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00634

AC:

770

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mucopolysaccharidosis, MPS-III-B

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0099

T;T

MetaSVM

Uncertain

-0.084

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

N;.

REVEL

Pathogenic

0.84

Sift

Benign

0.18

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.97

D;.

Vest4

0.70

MVP

0.98

MPC

1.1

ClinPred

0.017

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.94

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