17-42544215-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.635

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]

ACMG classification

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	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	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.: 31

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

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.: 74 AF XY: 0.922 AC XY: 668959 AN XY: 725748

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.: 31 AF XY: 0.852 AC XY: 63363 AN XY: 74352

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B Benign:4

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.36
Sift	Benign	0.042	D
Sift4G	Benign	0.067	T
Polyphen		0.68	P
Vest4		0.14
MPC		0.60
ClinPred		0.013	T
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

Other links and lift over

dbSNP: rs86312; hg19: chr17-40696233; COSMIC: COSV56795682; COSMIC: COSV56795682;