rs147293270

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000263.4(NAGLU):c.1438G>A(p.Ala480Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,597,670 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 0.190

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018946618).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000833 (127/152390) while in subpopulation NFE AF= 0.00126 (86/68034). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4 linkuse as main transcript	c.1438G>A	p.Ala480Thr	missense_variant	6/6	ENST00000225927.7	NP_000254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NAGLU	ENST00000225927.7 linkuse as main transcript	c.1438G>A	p.Ala480Thr	missense_variant	6/6	1	NM_000263.4	ENSP00000225927	P1
NAGLU	ENST00000591587.1 linkuse as main transcript	c.*407G>A		3_prime_UTR_variant	4/4	5		ENSP00000467836
NAGLU	ENST00000592454.1 linkuse as main transcript	c.*281G>A		3_prime_UTR_variant	2/2	2		ENSP00000468665

Frequencies

GnomAD3 genomes

AF:

0.000834

AC:

127

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000742

AC:

163

AN:

219550

Hom.:

AF XY:

0.000778

AC XY:

AN XY:

119500

show subpopulations

Gnomad AFR exome

AF:

0.000364

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00211

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000141

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000725

GnomAD4 exome

AF:

0.00105

AC:

1517

AN:

1445280

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

781

AN XY:

718100

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.000543

Gnomad4 ASJ exome

AF:

0.00197

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000828

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000719

GnomAD4 genome

AF:

0.000833

AC:

127

AN:

152390

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000858

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000751

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Mucopolysaccharidosis, MPS-III-B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

3.6

DANN

Benign

0.56

DEOGEN2

Uncertain

0.55

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.28

M_CAP

Benign

0.079

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

0.26

REVEL

Benign

0.19

Sift

Benign

0.81

Sift4G

Benign

0.60

Polyphen

0.038

Vest4

0.054

MVP

0.70

MPC

0.36

ClinPred

0.00095

GERP RS

-0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.32

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