17-42544215-C-A

Position:

chr17-42544215-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000263.4(NAGLU):c.2209C>A(p.Arg737Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,610,882 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R737G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 31)

Exomes 𝑓: 0.020 ( 341 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.635

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029644072).

BP6

Variant 17-42544215-C-A is Benign according to our data. Variant chr17-42544215-C-A is described in ClinVar as [Benign]. Clinvar id is 92692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42544215-C-A is described in Lovd as [Benign]. Variant chr17-42544215-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0146 (2220/152118) while in subpopulation SAS AF= 0.0309 (149/4824). AF 95% confidence interval is 0.0268. There are 26 homozygotes in gnomad4. There are 1135 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGLU	NM_000263.4 linkuse as main transcript	c.2209C>A	p.Arg737Ser	missense_variant	6/6	ENST00000225927.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGLU	ENST00000225927.7 linkuse as main transcript	c.2209C>A	p.Arg737Ser	missense_variant	6/6	1	NM_000263.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2221

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0309

Gnomad FIN

AF:

0.0269

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0184

AC:

4553

AN:

247800

Hom.:

AF XY:

0.0198

AC XY:

2659

AN XY:

134278

show subpopulations

Gnomad AFR exome

AF:

0.00361

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.00697

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0361

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0182

GnomAD4 exome

AF:

0.0197

AC:

28690

AN:

1458764

Hom.:

341

Cov.:

AF XY:

0.0202

AC XY:

14625

AN XY:

725758

show subpopulations

Gnomad4 AFR exome

AF:

0.00257

Gnomad4 AMR exome

AF:

0.00599

Gnomad4 ASJ exome

AF:

0.00738

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0348

Gnomad4 FIN exome

AF:

0.0252

Gnomad4 NFE exome

AF:

0.0205

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0146

AC:

2220

AN:

152118

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1135

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00357

Gnomad4 AMR

AF:

0.00759

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0309

Gnomad4 FIN

AF:

0.0269

Gnomad4 NFE

AF:

0.0210

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0173

Hom.:

6616

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0195

AC:

ExAC

AF:

0.0192

AC:

2325

EpiCase

AF:

0.0192

EpiControl

AF:

0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	NAGLU: BS1, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2017	- -

Mucopolysaccharidosis, MPS-III-B

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 23, 2013

- -

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

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.088

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0030

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.99

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.19

REVEL

Uncertain

0.37

Sift

Benign

0.049

Sift4G

Benign

0.081

Polyphen

0.47

Vest4

0.089

MPC

0.47

ClinPred

0.021

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.26

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