rs2092905670

Variant names:

• chr17-42536286-C-T
• rs2092905670
• NM_000263.4:c.14C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000263.4(NAGLU):​c.14C>T​(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 1,065,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.588
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease axonal type 2V

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000266929 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14322218).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	NM_000263.4	MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 6	NP_000254.2	A0A140VJE4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.14C>T	p.Ala5Val	missense	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.14C>T	p.Ala5Val	missense	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000751 AC: 8 AN: 1065214 Hom.: 0 Cov.: 30 AF XY: 0.00000795 AC XY: 4 AN XY: 503108

African (AFR) AF: 0.000180 AC: 4 AN: 22248

American (AMR) AF: 0.00 AC: 0 AN: 7890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13632

East Asian (EAS) AF: 0.00 AC: 0 AN: 25230

South Asian (SAS) AF: 0.00 AC: 0 AN: 19404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2830

European-Non Finnish (NFE) AF: 0.00000439 AC: 4 AN: 910698

Other (OTH) AF: 0.00 AC: 0 AN: 42578

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mucopolysaccharidosis, MPS-III-B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	5.1
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.20	N
PhyloP100		-0.59
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.21
Sift	Benign	0.20	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.41		Loss of helix (P = 0.0068)
MVP		0.63
MPC		0.36
ClinPred		0.095	T
GERP RS		-3.9
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.030
gMVP		0.46
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs2092905670; hg19: chr17-40688304;