rs86312

chr17-42544215-C-Achr17-42544215-C-Gchr17-42544215-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• 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=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 GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGLU	NM_000263.4	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	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.: 26 Cov.: 31

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.: 67 AF XY: 0.0198 AC XY: 2659 AN XY: 134278

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.: 74 AF XY: 0.0202 AC XY: 14625 AN XY: 725758

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.: 26 Cov.: 31 AF XY: 0.0153 AC XY: 1135 AN XY: 74362

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: 70

ALSPAC AF: 0.0195 AC: 75

ExAC AF: 0.0192 AC: 2325

EpiCase AF: 0.0192

EpiControl AF: 0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Mucopolysaccharidosis, MPS-III-B Benign:3

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

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0030	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.37
Sift	Benign	0.049	D
Sift4G	Benign	0.081	T
Polyphen		0.47	P
Vest4		0.089
MPC		0.47
ClinPred		0.021	T
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

Other links and lift over

dbSNP: rs86312; hg19: chr17-40696233; COSMIC: COSV56795278; COSMIC: COSV56795278;