17-42538671-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000263.4(NAGLU):āc.680A>Cā(p.His227Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000263.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.680A>C | p.His227Pro | missense_variant, splice_region_variant | 4/6 | ENST00000225927.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.680A>C | p.His227Pro | missense_variant, splice_region_variant | 4/6 | 1 | NM_000263.4 | P1 | |
NAGLU | ENST00000586516.5 | c.284A>C | p.His95Pro | missense_variant, splice_region_variant | 3/4 | 2 | |||
NAGLU | ENST00000591587.1 | c.275A>C | p.His92Pro | missense_variant, splice_region_variant | 3/4 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251014Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461636Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727134
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2023 | Variant summary: NAGLU c.680A>C (p.His227Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251014 control chromosomes (gnomAD). c.680A>C has been reported in the literature as a compound heterozygous genotype in an individual affected with attenuated Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (Weber_1999). Experimental evidence evaluating an impact on protein function in vitro found that the variant results in <10% of normal activity (Clark_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29979746, 10094189). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 14, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at