chr1-160343471-C-T
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2
The NM_015331.3(NCSTN):c.75C>T(p.Val25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,609,652 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 Likely benign (★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
NCSTN
NM_015331.3 synonymous
NM_015331.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.350
Genes affected
NCSTN (HGNC:17091): (nicastrin) This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014]
COPA (HGNC:2230): (COPI coat complex subunit alpha) In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs). Seven coat proteins have been identified, and they represent subunits of a complex known as coatomer. The subunits are designated alpha-COP, beta-COP, beta-prime-COP, gamma-COP, delta-COP, epsilon-COP, and zeta-COP. The alpha-COP, encoded by COPA, shares high sequence similarity with RET1P, the alpha subunit of the coatomer complex in yeast. Also, the N-terminal 25 amino acids of alpha-COP encode the bioactive peptide, xenin, which stimulates exocrine pancreatic secretion and may act as a gastrointestinal hormone. Alternative splicing results in multiple splice forms encoding distinct isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
Variant 1-160343471-C-T is Benign according to our data. Variant chr1-160343471-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1602908.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.35 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000986 (15/152178) while in subpopulation NFE AF= 0.00022 (15/68028). AF 95% confidence interval is 0.000135. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NCSTN | NM_015331.3 | c.75C>T | p.Val25= | synonymous_variant | 1/17 | ENST00000294785.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NCSTN | ENST00000294785.10 | c.75C>T | p.Val25= | synonymous_variant | 1/17 | 1 | NM_015331.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152178Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000208 AC: 5AN: 240136Hom.: 0 AF XY: 0.0000309 AC XY: 4AN XY: 129436
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GnomAD4 exome AF: 0.0000213 AC: 31AN: 1457474Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16AN XY: 724554
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GnomAD4 genome AF: 0.0000986 AC: 15AN: 152178Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74338
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2022 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at