9-85958589-A-G
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_024635.4(NAA35):c.273+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,586,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00048 ( 1 hom. )
Consequence
NAA35
NM_024635.4 splice_donor_region, intron
NM_024635.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9831
2
Clinical Significance
Conservation
PhyloP100: 1.63
Genes affected
NAA35 (HGNC:24340): (N-alpha-acetyltransferase 35, NatC auxiliary subunit) Involved in negative regulation of apoptotic process. Located in cytosol; nucleoplasm; and plasma membrane. Part of NatC complex. Colocalizes with polysome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BS2
High AC in GnomAd4 at 41 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAA35 | NM_024635.4 | c.273+3A>G | splice_donor_region_variant, intron_variant | ENST00000361671.10 | |||
NAA35 | NM_001321881.2 | c.273+3A>G | splice_donor_region_variant, intron_variant | ||||
NAA35 | NM_001321882.2 | c.273+3A>G | splice_donor_region_variant, intron_variant | ||||
NAA35 | XM_005252127.5 | c.273+3A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAA35 | ENST00000361671.10 | c.273+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_024635.4 | P1 | |||
NAA35 | ENST00000376040.2 | c.273+3A>G | splice_donor_region_variant, intron_variant | 2 | |||||
NAA35 | ENST00000416045.4 | n.370+3A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000269 AC: 41AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000373 AC: 91AN: 243790Hom.: 1 AF XY: 0.000471 AC XY: 62AN XY: 131716
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GnomAD4 exome AF: 0.000479 AC: 687AN: 1434008Hom.: 1 Cov.: 24 AF XY: 0.000507 AC XY: 362AN XY: 714644
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GnomAD4 genome AF: 0.000269 AC: 41AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change falls in intron 4 of the NAA35 gene. It does not directly change the encoded amino acid sequence of the NAA35 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367602279, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NAA35-related conditions. ClinVar contains an entry for this variant (Variation ID: 2058140). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at