rs1445294968

Variant names:

• chr17-42536630-G-T
• rs1445294968
• NM_000263.4:c.358G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-42536630-G-T
• chr17-42536630-G-A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000263.4(NAGLU):​c.358G>T​(p.Glu120*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 1,347,404 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: NAGLU NM_000263.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.568
• 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42536630-G-T is Pathogenic according to our data. Variant chr17-42536630-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 552642.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.358G>T	p.Glu120*	stop_gained	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.358G>T	p.Glu120*	stop_gained	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.358G>T	p.Glu120*	stop_gained	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.358G>T	p.Glu120*	stop_gained	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000371 AC: 5 AN: 1347404 Hom.: 0 Cov.: 30 AF XY: 0.00000452 AC XY: 3 AN XY: 664274

African (AFR) AF: 0.00 AC: 0 AN: 27568

American (AMR) AF: 0.00 AC: 0 AN: 31460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23896

East Asian (EAS) AF: 0.00 AC: 0 AN: 31236

South Asian (SAS) AF: 0.00 AC: 0 AN: 75572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4782

European-Non Finnish (NFE) AF: 0.00000470 AC: 5 AN: 1063750

Other (OTH) AF: 0.00 AC: 0 AN: 56092

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Mucopolysaccharidosis, MPS-III-B (3)
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	Benign	0.13
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Benign	-0.00089
FATHMM_MKL	Benign	0.57	D
PhyloP100		0.57
Vest4		0.41
GERP RS		1.4
PromoterAI		-0.0010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1445294968; hg19: chr17-40688648;