17-42536615-C-G

Variant names:

• chr17-42536615-C-G
• rs758785463
• NM_000263.4:c.343C>G
• NAGLU p.Pro115Ala

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000263.4(NAGLU):​c.343C>G​(p.Pro115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,342,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P115S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• 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: Myriad Women's Health, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet
• Charcot-Marie-Tooth disease axonal type 2V

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

ENSG00000266929 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42536615-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 553505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

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.343C>G	p.Pro115Ala	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.343C>G	p.Pro115Ala	missense	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.343C>G	p.Pro115Ala	missense	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.343C>G	p.Pro115Ala	missense	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1342270 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 661966

African (AFR) AF: 0.00 AC: 0 AN: 27150

American (AMR) AF: 0.00 AC: 0 AN: 30078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23638

East Asian (EAS) AF: 0.00 AC: 0 AN: 30876

South Asian (SAS) AF: 0.00 AC: 0 AN: 74744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4836

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1062210

Other (OTH) AF: 0.00 AC: 0 AN: 55838

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.25	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.90	D
PhyloP100		1.7
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
Mutation Taster		=69/31	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs758785463;

hg19: chr17-40688633;