17-42536277-A-AGGCGGT
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1
The NM_000263.4(NAGLU):c.15_20dupGGTGGC(p.Ala7_Ala8insValAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,217,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000263.4 disruptive_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.15_20dupGGTGGC | p.Ala7_Ala8insValAla | disruptive_inframe_insertion | Exon 1 of 6 | ENST00000225927.7 | NP_000254.2 | |
NAGLU | XM_024450771.2 | c.15_20dupGGTGGC | p.Ala7_Ala8insValAla | disruptive_inframe_insertion | Exon 1 of 7 | XP_024306539.1 | ||
NAGLU | XM_047436138.1 | c.-447_-442dupGGTGGC | 5_prime_UTR_variant | Exon 1 of 5 | XP_047292094.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000553 AC: 84AN: 152036Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000507 AC: 54AN: 1065536Hom.: 0 Cov.: 30 AF XY: 0.0000517 AC XY: 26AN XY: 503220
GnomAD4 genome AF: 0.000552 AC: 84AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40AN XY: 74374
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided Uncertain:1
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not specified Benign:1
Variant summary: NAGLU c.15_20dupGGTGGC (p.Val6_Ala7dup) results in an in-frame duplication that is predicted to duplicate two amino acids into the encoded protein. The variant allele was found at a frequency of 0.00077 in 31166 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in NAGLU causing Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.15_20dupGGTGGC in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One lab classified as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
NAGLU-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at