19-13135340-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The ENST00000292431.5(NACC1):​c.133C>T​(p.Arg45Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NACC1
ENST00000292431.5 missense

Scores

13
3
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 6.09
Variant links:
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 Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NACC1. . Gene score misZ 4.1668 (greater than the threshold 3.09). Trascript score misZ 3.946 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953
PP5
Variant 19-13135340-C-T is Pathogenic according to our data. Variant chr19-13135340-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451782.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NACC1NM_052876.4 linkuse as main transcriptc.133C>T p.Arg45Trp missense_variant 2/6 ENST00000292431.5 NP_443108.1
NACC1XM_005259721.4 linkuse as main transcriptc.133C>T p.Arg45Trp missense_variant 3/7 XP_005259778.1
NACC1XM_047438118.1 linkuse as main transcriptc.133C>T p.Arg45Trp missense_variant 2/6 XP_047294074.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NACC1ENST00000292431.5 linkuse as main transcriptc.133C>T p.Arg45Trp missense_variant 2/61 NM_052876.4 ENSP00000292431 P1
NACC1ENST00000586171.3 linkuse as main transcriptc.133C>T p.Arg45Trp missense_variant 3/75 ENSP00000467120 P1
NACC1ENST00000700232.1 linkuse as main transcriptc.133C>T p.Arg45Trp missense_variant 2/6 ENSP00000514870 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461324
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726984
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxMay 17, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159) -
Neurodevelopmental disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesNov 03, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D;D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Benign
-0.47
T
MutationAssessor
Pathogenic
3.4
.;M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.8
.;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.91
MutPred
0.84
Gain of catalytic residue at R45 (P = 0.0382);Gain of catalytic residue at R45 (P = 0.0382);
MVP
0.76
MPC
2.5
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.89
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555722264; hg19: chr19-13246154; API