9-85962100-A-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_024635.4(NAA35):c.436A>G(p.Met146Val) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00058 ( 2 hom., cov: 31)
Exomes 𝑓: 0.00035 ( 2 hom. )
Consequence
NAA35
NM_024635.4 missense
NM_024635.4 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 6.14
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 -5 ACMG points.
PP2
Missense variant where missense usually causes diseases, NAA35
BP4
Computational evidence support a benign effect (MetaRNN=0.07501307).
BS2
High AC in GnomAd4 at 88 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAA35 | NM_024635.4 | c.436A>G | p.Met146Val | missense_variant | 6/23 | ENST00000361671.10 | |
NAA35 | NM_001321881.2 | c.436A>G | p.Met146Val | missense_variant | 6/23 | ||
NAA35 | NM_001321882.2 | c.436A>G | p.Met146Val | missense_variant | 6/23 | ||
NAA35 | XM_005252127.5 | c.436A>G | p.Met146Val | missense_variant | 6/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAA35 | ENST00000361671.10 | c.436A>G | p.Met146Val | missense_variant | 6/23 | 1 | NM_024635.4 | P1 | |
NAA35 | ENST00000376040.2 | c.436A>G | p.Met146Val | missense_variant | 6/12 | 2 | |||
NAA35 | ENST00000416045.4 | n.533A>G | non_coding_transcript_exon_variant | 6/7 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000578 AC: 88AN: 152202Hom.: 2 Cov.: 31
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GnomAD3 exomes AF: 0.000473 AC: 119AN: 251450Hom.: 0 AF XY: 0.000508 AC XY: 69AN XY: 135900
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GnomAD4 exome AF: 0.000348 AC: 508AN: 1461846Hom.: 2 Cov.: 30 AF XY: 0.000367 AC XY: 267AN XY: 727234
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GnomAD4 genome AF: 0.000578 AC: 88AN: 152320Hom.: 2 Cov.: 31 AF XY: 0.000645 AC XY: 48AN XY: 74472
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2021 | The c.436A>G (p.M146V) alteration is located in exon 6 (coding exon 5) of the NAA35 gene. This alteration results from a A to G substitution at nucleotide position 436, causing the methionine (M) at amino acid position 146 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 146 of the NAA35 protein (p.Met146Val). This variant is present in population databases (rs149812553, gnomAD 0.1%), 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: 2160633). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at