19-35746494-C-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_172341.4(PSENEN):c.137C>A(p.Ala46Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_172341.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PSENEN | NM_172341.4 | c.137C>A | p.Ala46Asp | missense_variant | 3/4 | ENST00000587708.7 | NP_758844.1 | |
PSENEN | NM_001281532.3 | c.137C>A | p.Ala46Asp | missense_variant | 3/4 | NP_001268461.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PSENEN | ENST00000587708.7 | c.137C>A | p.Ala46Asp | missense_variant | 3/4 | 1 | NM_172341.4 | ENSP00000468411.1 | ||
PSENEN | ENST00000222266.2 | c.137C>A | p.Ala46Asp | missense_variant | 3/4 | 1 | ENSP00000222266.1 | |||
ENSG00000188223 | ENST00000591613.2 | n.137C>A | non_coding_transcript_exon_variant | 3/11 | 2 | ENSP00000468389.2 | ||||
PSENEN | ENST00000591949.1 | c.137C>A | p.Ala46Asp | missense_variant | 3/3 | 2 | ENSP00000468593.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251378Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135878
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461674Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727154
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 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. This variant is present in population databases (rs749446715, ExAC 0.02%). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PSENEN-related conditions. This sequence change replaces alanine with aspartic acid at codon 46 of the PSENEN protein (p.Ala46Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at