rs1553211087

Positions:

• chr1-160356711-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015331.3(NCSTN):​c.1752delG​(p.Glu584fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCSTN NM_015331.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.393

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-160356711-AG-A is Pathogenic according to our data. Variant chr1-160356711-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 30452.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-160356711-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCSTN	NM_015331.3	c.1752delG	p.Glu584fs	frameshift_variant	15/17	ENST00000294785.10	NP_056146.1
NCSTN	NM_001290184.2	c.1692delG	p.Glu564fs	frameshift_variant	16/18		NP_001277113.1
NCSTN	NM_001349729.2	c.1752delG	p.Glu584fs	frameshift_variant	15/16		NP_001336658.1
NCSTN	NM_001290186.2	c.1338delG	p.Glu446fs	frameshift_variant	12/14		NP_001277115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCSTN	ENST00000294785.10	c.1752delG	p.Glu584fs	frameshift_variant	15/17	1	NM_015331.3	ENSP00000294785.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acne inversa, familial, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 19, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1553211087; hg19: chr1-160326501;