rs886043785

Positions:

• chr17-42537436-C-A
• chr17-42537436-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000263.4(NAGLU):​c.422C>A​(p.Ser141Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S141T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4	c.422C>A	p.Ser141Tyr	missense_variant	2/6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2	c.479C>A	p.Ser160Tyr	missense_variant	3/7		XP_024306539.1
NAGLU	XM_047436138.1	c.-79+781C>A		intron_variant			XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.422C>A	p.Ser141Tyr	missense_variant	2/6	1	NM_000263.4	ENSP00000225927.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.86		Gain of sheet (P = 0.039);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886043785; hg19: chr17-40689454;