rs104894599

Variant names:

• chr17-42536416-C-A
• rs104894599
• NM_000263.4:c.144C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-42536416-C-A
• chr17-42536416-C-G
• chr17-42536416-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1_Very_Strong PM1 PP3_Strong PP5_Moderate

The NM_000263.4(NAGLU):​c.144C>A​(p.Phe48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,098,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F48F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.253
• Publications: 5 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: Pathogenic. The variant received 16 ACMG points.

• PS1: Transcript NM_000263.4 (NAGLU) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a strand (size 4) in uniprot entity ANAG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000263.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 17-42536416-C-A is Pathogenic according to our data. Variant chr17-42536416-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2138021.Status of the report is criteria_provided_single_submitter, 1 stars.

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.144C>A	p.Phe48Leu	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.144C>A	p.Phe48Leu	missense	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.144C>A	p.Phe48Leu	missense	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.144C>A	p.Phe48Leu	missense	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000301 AC: 33 AN: 1098134 Hom.: 0 Cov.: 30 AF XY: 0.0000263 AC XY: 14 AN XY: 531702

African (AFR) AF: 0.00 AC: 0 AN: 22160

American (AMR) AF: 0.00 AC: 0 AN: 17018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16432

East Asian (EAS) AF: 0.00 AC: 0 AN: 19570

South Asian (SAS) AF: 0.0000269 AC: 1 AN: 37228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2938

European-Non Finnish (NFE) AF: 0.0000348 AC: 32 AN: 919456

Other (OTH) AF: 0.00 AC: 0 AN: 42054

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.25
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.73
Sift	Benign	0.034	D
Sift4G	Benign	0.10	T
Polyphen		0.98	D
Vest4		0.74
MutPred		0.86		Gain of disorder (P = 0.0662)
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		3.4
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.82
gMVP		0.76
Mutation Taster		=30/70	disease causing

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: rs104894599; hg19: chr17-40688434;