chr17-42544215-C-G

Position:

chr17-42544215-C-G

Variant summary

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

The NM_000263.4(NAGLU):c.2209C>G(p.Arg737Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 1,610,842 control chromosomes in the GnomAD database, including 676,272 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. R737S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.85 ( 56290 hom., cov: 31)

Exomes 𝑓: 0.92 ( 619982 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

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=9.1667613E-7).

BP6

Variant 17-42544215-C-G is Benign according to our data. Variant chr17-42544215-C-G is described in ClinVar as [Benign]. Clinvar id is 92693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42544215-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGLU	NM_000263.4 linkuse as main transcript	c.2209C>G	p.Arg737Gly	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>G	p.Arg737Gly	missense_variant	6/6	1	NM_000263.4	P1

Frequencies

GnomAD3 genomes

AF:

0.852

AC:

129502

AN:

151990

Hom.:

56251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.887

Gnomad AMR

AF:

0.916

Gnomad ASJ

AF:

0.928

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.938

Gnomad FIN

AF:

0.871

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.925

Gnomad OTH

AF:

0.870

GnomAD3 exomes

AF:

0.911

AC:

225684

AN:

247800

Hom.:

103413

AF XY:

0.915

AC XY:

122855

AN XY:

134278

show subpopulations

Gnomad AFR exome

AF:

0.653

Gnomad AMR exome

AF:

0.946

Gnomad ASJ exome

AF:

0.929

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.930

Gnomad FIN exome

AF:

0.874

Gnomad NFE exome

AF:

0.922

Gnomad OTH exome

AF:

0.911

GnomAD4 exome

AF:

0.921

AC:

1343303

AN:

1458734

Hom.:

619982

Cov.:

AF XY:

0.922

AC XY:

668959

AN XY:

725748

show subpopulations

Gnomad4 AFR exome

AF:

0.652

Gnomad4 AMR exome

AF:

0.942

Gnomad4 ASJ exome

AF:

0.930

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.929

Gnomad4 FIN exome

AF:

0.878

Gnomad4 NFE exome

AF:

0.927

Gnomad4 OTH exome

AF:

0.911

GnomAD4 genome

AF:

0.852

AC:

129597

AN:

152108

Hom.:

56290

Cov.:

AF XY:

0.852

AC XY:

63363

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.667

Gnomad4 AMR

AF:

0.916

Gnomad4 ASJ

AF:

0.928

Gnomad4 EAS

AF:

0.997

Gnomad4 SAS

AF:

0.937

Gnomad4 FIN

AF:

0.871

Gnomad4 NFE

AF:

0.926

Gnomad4 OTH

AF:

0.871

Alfa

AF:

0.861

Hom.:

6616

Bravo

AF:

0.855

TwinsUK

AF:

0.934

AC:

3464

ALSPAC

AF:

0.929

AC:

3580

ESP6500AA

AF:

0.662

AC:

2916

ESP6500EA

AF:

0.945

AC:

8124

ExAC

AF:

0.905

AC:

109804

EpiCase

AF:

0.919

EpiControl

AF:

0.918

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2016	Variant summary: The NAGLU c.2209C>G (p.Arg737Gly) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant, however they are not definite. This variant was found in 108969/120346 control chromosomes (including 49702 homozygotes) at a frequency of 0.9054642, which is approximately 362 times the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025), thus showing that this variant is a benign polymorphism and allele G is an ancestral allele. In addition, clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, based on the prevalence in the general population this variant is classified as benign. -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Charcot-Marie-Tooth disease axonal type 2V

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

0.099

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.083

Eigen_PC

Benign

-0.019

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.48

MetaRNN

Benign

9.2e-7

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.99

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.36

Sift

Benign

0.042

Sift4G

Benign

0.067

Polyphen

0.68

Vest4

0.14

MPC

0.60

ClinPred

0.013

GERP RS

4.0

Varity_R

0.21

gMVP

0.24

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