17-42536274-T-TGGAGGC

Variant names:

• chr17-42536274-T-TGGAGGC
• rs1555621396
• NM_000263.4:c.5_10dupAGGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000263.4(NAGLU):​c.5_10dupAGGCGG​(p.Glu2_Ala3dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. V4V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAGLU NM_000263.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.984
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.5_10dupAGGCGG	p.Glu2_Ala3dup	disruptive_inframe_insertion	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.5_10dupAGGCGG	p.Glu2_Ala3dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.5_10dupAGGCGG	p.Glu2_Ala3dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.5_10dupAGGCGG	p.Glu2_Ala3dup	disruptive_inframe_insertion	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000188 AC: 2 AN: 1064954 Hom.: 0 Cov.: 30 AF XY: 0.00000398 AC XY: 2 AN XY: 502992

African (AFR) AF: 0.00 AC: 0 AN: 22234

American (AMR) AF: 0.00 AC: 0 AN: 7898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13614

East Asian (EAS) AF: 0.00 AC: 0 AN: 25224

South Asian (SAS) AF: 0.00 AC: 0 AN: 19412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2826

European-Non Finnish (NFE) AF: 0.00000220 AC: 2 AN: 910492

Other (OTH) AF: 0.00 AC: 0 AN: 42568

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Mucopolysaccharidosis, MPS-III-B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98

Splicing

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

Other links and lift over

dbSNP: rs1555621396; hg19: chr17-40688292;