rs1009493804
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_052876.4(NACC1):c.365A>G(p.Lys122Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000561 in 1,605,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
NACC1
NM_052876.4 missense
NM_052876.4 missense
Scores
6
9
Clinical Significance
Conservation
PhyloP100: 7.19
Genes affected
NACC1 (HGNC:20967): (nucleus accumbens associated 1) This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance. The encoded protein also suppresses transcription of the candidate tumor suppressor Gadd45GIP1, and expression of this gene may play a role in the progression of multiple types of cancer. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, NACC1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.29354376).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NACC1 | NM_052876.4 | c.365A>G | p.Lys122Arg | missense_variant | 2/6 | ENST00000292431.5 | |
NACC1 | XM_005259721.4 | c.365A>G | p.Lys122Arg | missense_variant | 3/7 | ||
NACC1 | XM_047438118.1 | c.365A>G | p.Lys122Arg | missense_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NACC1 | ENST00000292431.5 | c.365A>G | p.Lys122Arg | missense_variant | 2/6 | 1 | NM_052876.4 | P1 | |
NACC1 | ENST00000586171.3 | c.365A>G | p.Lys122Arg | missense_variant | 3/7 | 5 | P1 | ||
NACC1 | ENST00000700232.1 | c.365A>G | p.Lys122Arg | missense_variant | 2/6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000429 AC: 1AN: 233036Hom.: 0 AF XY: 0.00000788 AC XY: 1AN XY: 126920
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GnomAD4 exome AF: 0.00000413 AC: 6AN: 1453418Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4AN XY: 722674
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 11, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 122 of the NACC1 protein (p.Lys122Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with NACC1-related conditions (PMID: 31618753). ClinVar contains an entry for this variant (Variation ID: 521628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NACC1 protein function with a negative predictive value of 80%. 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
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Benign
T;D
Polyphen
0.39
.;B
Vest4
0.45
MVP
MPC
1.3
ClinPred
D
GERP RS
Varity_R
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