17-42536480-G-T

Variant names:

• chr17-42536480-G-T
• rs1329159364
• NM_000263.4:c.208G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000263.4(NAGLU):​c.208G>T​(p.Gly70Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,064,384 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. G70R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	NM_000263.4	MANE Select	c.208G>T	p.Gly70Cys	missense	Exon 1 of 6	NP_000254.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.208G>T	p.Gly70Cys	missense	Exon 1 of 6	ENSP00000225927.1
	NAGLU	ENST00000586516.5	TSL:2	c.-44G>T		upstream_gene	N/A	ENSP00000467135.1
	NAGLU	ENST00000591587.1	TSL:5	c.-50G>T		upstream_gene	N/A	ENSP00000467836.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1064384 Hom.: 0 Cov.: 30 AF XY: 0.00000196 AC XY: 1 AN XY: 510232

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21288

American (AMR) AF: 0.000126 AC: 1 AN: 7960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13374

East Asian (EAS) AF: 0.00 AC: 0 AN: 21400

South Asian (SAS) AF: 0.00 AC: 0 AN: 24666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2866

European-Non Finnish (NFE) AF: 0.00000110 AC: 1 AN: 911388

Other (OTH) AF: 0.00 AC: 0 AN: 41198

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.60
Sift	Benign	0.046	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.51
MutPred		0.62		Loss of disorder (P = 0.0179)
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.070	Neutral
Varity_R		0.85
gMVP		0.59

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: rs1329159364; hg19: chr17-40688498;