17-42536286-C-T

Position:

• chr17-42536286-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14322218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4	c.14C>T	p.Ala5Val	missense_variant	1/6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2	c.14C>T	p.Ala5Val	missense_variant	1/7		XP_024306539.1
NAGLU	XM_047436138.1	c.-448C>T		5_prime_UTR_variant	1/5		XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.14C>T	p.Ala5Val	missense_variant	1/6	1	NM_000263.4	ENSP00000225927.1

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

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000439

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 17, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.030
gMVP		0.46

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: rs2092905670; hg19: chr17-40688304;