17-42537437-T-C

Position:

• chr17-42537437-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000263.4(NAGLU):​c.423T>C​(p.Ser141Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,614,250 control chromosomes in the GnomAD database, including 795,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75417 hom., cov: 35)
  • Exomes 𝑓: 0.99 (720564 hom.)
• Consequence: NAGLU NM_000263.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.790

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]

ENSG00000266929 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-42537437-T-C is Benign according to our data. Variant chr17-42537437-T-C is described in ClinVar as [Benign]. Clinvar id is 92694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42537437-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4	c.423T>C	p.Ser141Ser	synonymous_variant	2/6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2	c.480T>C	p.Ser160Ser	synonymous_variant	3/7		XP_024306539.1
NAGLU	XM_047436138.1	c.-79+782T>C		intron_variant			XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.423T>C	p.Ser141Ser	synonymous_variant	2/6	1	NM_000263.4	ENSP00000225927.1

Frequencies

GnomAD3 genomes AF: 0.995 AC: 151483 AN: 152254 Hom.: 75358 Cov.: 35

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.992

Gnomad OTH AF: 0.991

GnomAD3 exomes AF: 0.995 AC: 250086 AN: 251462 Hom.: 124362 AF XY: 0.994 AC XY: 135168 AN XY: 135916

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.998

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.992

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.993 AC: 1451456 AN: 1461878 Hom.: 720564 Cov.: 75 AF XY: 0.993 AC XY: 722157 AN XY: 727240

Gnomad4 AFR exome AF: 0.999

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 0.989

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.998

Gnomad4 FIN exome AF: 0.995

Gnomad4 NFE exome AF: 0.992

Gnomad4 OTH exome AF: 0.992

GnomAD4 genome AF: 0.995 AC: 151601 AN: 152372 Hom.: 75417 Cov.: 35 AF XY: 0.995 AC XY: 74141 AN XY: 74516

Gnomad4 AFR AF: 0.998

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 0.988

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.995

Gnomad4 NFE AF: 0.992

Gnomad4 OTH AF: 0.991

Alfa AF: 0.992 Hom.: 89963

Bravo AF: 0.995

Asia WGS AF: 0.999 AC: 3473 AN: 3478

EpiCase AF: 0.991

EpiControl AF: 0.991

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:4

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.423T>C (p.Ser141Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 120745/121388 control chromosomes (including 60052 homozygotes) at a frequency of 0.9947029, which is approximately 398 times the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025), showing that this variant is a benign polymorphism and allele C is an ancestral allele. In addition, clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease axonal type 2V Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

NAGLU-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs659497; hg19: chr17-40689455;