chr17-42543817-C-A

Variant names:

• chr17-42543817-C-A
• NM_000263.4:c.1811C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000263.4(NAGLU):​c.1811C>A​(p.Pro604Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,451,210 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. P604L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89

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]

ENSG00000266929 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42543817-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGLU	NM_000263.4	c.1811C>A	p.Pro604Gln	missense_variant	Exon 6 of 6	ENST00000225927.7	NP_000254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.1811C>A	p.Pro604Gln	missense_variant	Exon 6 of 6	1	NM_000263.4	ENSP00000225927.1
NAGLU	ENST00000591587.1	c.*780C>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000467836.1
ENSG00000266929	ENST00000585572.1	n.379+5062C>A		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451210 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.62
Sift	Benign	0.55	T
Sift4G	Benign	0.61	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.44		Gain of helix (P = 0.0349);
MVP		0.97
MPC		0.89
ClinPred		0.78	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.30

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40695835;