rs7540865

Variant names:

• chr1-160351060-G-T
• rs7540865
• NM_015331.3:c.583-162G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015331.3(NCSTN):​c.583-162G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,966 control chromosomes in the GnomAD database, including 8,735 homozygotes. 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 0.33 (8735 hom., cov: 31)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCSTN	NM_015331.3	c.583-162G>T		intron_variant	Intron 5 of 16	ENST00000294785.10	NP_056146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCSTN	ENST00000294785.10	c.583-162G>T		intron_variant	Intron 5 of 16	1	NM_015331.3	ENSP00000294785.5

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50731 AN: 151848 Hom.: 8732 Cov.: 31

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.329

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.334 AC: 50759 AN: 151966 Hom.: 8735 Cov.: 31 AF XY: 0.329 AC XY: 24420 AN XY: 74298

African (AFR) AF: 0.393 AC: 16285 AN: 41388

American (AMR) AF: 0.344 AC: 5250 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 854 AN: 3466

East Asian (EAS) AF: 0.116 AC: 599 AN: 5174

South Asian (SAS) AF: 0.254 AC: 1227 AN: 4826

European-Finnish (FIN) AF: 0.295 AC: 3120 AN: 10564

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22188 AN: 67962

Other (OTH) AF: 0.325 AC: 685 AN: 2106

Alfa AF: 0.329 Hom.: 3900

Bravo AF: 0.347

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.8
DANN	Benign	0.72
PhyloP100		0.25
PromoterAI		0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7540865; hg19: chr1-160320850;