rs1431589133

Variant names:

• chr17-42536483-GGCGCGGCGCGCGTGCGGGT-G
• rs1431589133
• NM_000263.4:c.219_237delGCGCGTGCGGGTGCGCGGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000263.4(NAGLU):​c.219_237delGCGCGTGCGGGTGCGCGGC​(p.Arg74ProfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,067,176 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A73A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NAGLU NM_000263.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.44
• Publications: 1 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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-42536483-GGCGCGGCGCGCGTGCGGGT-G is Pathogenic according to our data. Variant chr17-42536483-GGCGCGGCGCGCGTGCGGGT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 554876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift	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.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000861 AC: 1 AN: 11614 AF XY: 0.000129

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 12 AN: 1067176 Hom.: 0 AF XY: 0.0000117 AC XY: 6 AN XY: 511482

African (AFR) AF: 0.00 AC: 0 AN: 21406

American (AMR) AF: 0.00 AC: 0 AN: 7982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13380

East Asian (EAS) AF: 0.00 AC: 0 AN: 21940

South Asian (SAS) AF: 0.00 AC: 0 AN: 24230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2912

European-Non Finnish (NFE) AF: 0.0000120 AC: 11 AN: 913454

Other (OTH) AF: 0.0000241 AC: 1 AN: 41448

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis, MPS-III-B (2)
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
PhyloP100		2.4
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1431589133; hg19: chr17-40688501;