1-160353563-A-T

Variant names:

• chr1-160353563-A-T
• rs1124379
• NM_015331.3:c.1179+326A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015331.3(NCSTN):​c.1179+326A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,922 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: not found (cov: 31)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562
• Publications: 0 publications found

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]

NCSTN Gene-Disease associations (from GenCC):

• acne inversa, familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCSTN	NM_015331.3	c.1179+326A>T		intron_variant	Intron 10 of 16	ENST00000294785.10	NP_056146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCSTN	ENST00000294785.10	c.1179+326A>T		intron_variant	Intron 10 of 16	1	NM_015331.3	ENSP00000294785.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096922 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 526702

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23602

American (AMR) AF: 0.00 AC: 0 AN: 13666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12448

East Asian (EAS) AF: 0.00 AC: 0 AN: 17266

South Asian (SAS) AF: 0.00 AC: 0 AN: 56574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2658

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 916284

Other (OTH) AF: 0.00 AC: 0 AN: 41310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.4
DANN	Benign	0.88
PhyloP100		-0.56

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

Other links and lift over

dbSNP: rs1124379; hg19: chr1-160323353;