19-35746709-T-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_172341.4(PSENEN):āc.168T>Gā(p.Tyr56Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
PSENEN
NM_172341.4 stop_gained, splice_region
NM_172341.4 stop_gained, splice_region
Scores
4
2
1
Splicing: ADA: 0.8909
1
1
Clinical Significance
Conservation
PhyloP100: 3.63
Genes affected
PSENEN (HGNC:30100): (presenilin enhancer, gamma-secretase subunit) Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer's disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.451 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSENEN | NM_172341.4 | c.168T>G | p.Tyr56Ter | stop_gained, splice_region_variant | 4/4 | ENST00000587708.7 | |
PSENEN | NM_001281532.3 | c.168T>G | p.Tyr56Ter | stop_gained, splice_region_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSENEN | ENST00000587708.7 | c.168T>G | p.Tyr56Ter | stop_gained, splice_region_variant | 4/4 | 1 | NM_172341.4 | P1 | |
PSENEN | ENST00000222266.2 | c.168T>G | p.Tyr56Ter | stop_gained, splice_region_variant | 4/4 | 1 | P1 | ||
PSENEN | ENST00000591949.1 | c.*58T>G | 3_prime_UTR_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727248
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1461892
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32
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AN XY:
727248
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GnomAD4 genome Cov.: 31
GnomAD4 genome
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31
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1
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 | May 26, 2021 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with clinical features of hidradenitis suppurativa and Dowling-Degos disease (PMID: 28922471). This variant is present in population databases (rs751542345, ExAC 0.001%). This sequence change results in a premature translational stop signal in the PSENEN gene (p.Tyr56*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the PSENEN protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at