rs751031803

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_001290184.2(NCSTN):​c.-145C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,611,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

NCSTN
NM_001290184.2 5_prime_UTR_premature_start_codon_gain

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.39
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16931108).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000336 (49/1459336) while in subpopulation NFE AF= 0.0000441 (49/1111266). AF 95% confidence interval is 0.0000337. There are 0 homozygotes in gnomad4_exome. There are 21 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 49 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NCSTNNM_015331.3 linkc.55C>G p.Arg19Gly missense_variant Exon 1 of 17 ENST00000294785.10 NP_056146.1 Q92542-1
COPANM_004371.4 linkc.-281G>C upstream_gene_variant ENST00000241704.8 NP_004362.2 P53621-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NCSTNENST00000294785.10 linkc.55C>G p.Arg19Gly missense_variant Exon 1 of 17 1 NM_015331.3 ENSP00000294785.5 Q92542-1
COPAENST00000241704.8 linkc.-281G>C upstream_gene_variant 1 NM_004371.4 ENSP00000241704.7 P53621-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152132
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000820
AC:
2
AN:
243880
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131540
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000182
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000336
AC:
49
AN:
1459336
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
725686
show subpopulations
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:
0.0000441
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152132
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Uncertain
0.063
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.22
T;T;T;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.73
T;T;T;T
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.17
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;.;.
PrimateAI
Benign
0.45
T
PROVEAN
Benign
0.050
N;N;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.34
T;T;T;D
Sift4G
Benign
0.24
T;T;T;T
Polyphen
0.039
B;.;.;.
Vest4
0.52
MutPred
0.67
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
0.93
MPC
0.087
ClinPred
0.13
T
GERP RS
2.9
Varity_R
0.15
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs751031803; hg19: chr1-160313241; API