17-42536416-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000263.4(NAGLU):​c.144C>T​(p.Phe48Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAGLU NM_000263.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B: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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-42536416-C-T is Benign according to our data. Variant chr17-42536416-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1610841.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.253 with no splicing effect.

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>T	p.Phe48Phe	synonymous	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>T	p.Phe48Phe	synonymous	Exon 1 of 6	ENSP00000225927.1	P54802
	NAGLU	ENST00000963429.1		c.144C>T	p.Phe48Phe	synonymous	Exon 1 of 6	ENSP00000633488.1
	NAGLU	ENST00000904921.1		c.144C>T	p.Phe48Phe	synonymous	Exon 1 of 7	ENSP00000574980.1

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149906 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098134 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 919456

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

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149906 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73134

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

African (AFR) AF: 0.00 AC: 0 AN: 41184

American (AMR) AF: 0.00 AC: 0 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67160

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.25
PromoterAI		0.015	Neutral

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;