NM_015331.3:c.191-1669T>G

Variant names:

• chr1-160347330-T-G
• rs10494342
• NM_015331.3:c.191-1669T>G

Variant summary

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

The NM_015331.3(NCSTN):​c.191-1669T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,264 control chromosomes in the GnomAD database, including 1,343 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 0.10 (1343 hom., cov: 32)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 8 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015331.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	NM_015331.3	MANE Select	c.191-1669T>G		intron	N/A	NP_056146.1
	NCSTN	NM_001290184.2		c.131-1669T>G		intron	N/A	NP_001277113.1
	NCSTN	NM_001349729.2		c.191-1669T>G		intron	N/A	NP_001336658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.191-1669T>G		intron	N/A	ENSP00000294785.5
	NCSTN	ENST00000368063.6	TSL:1	n.*120-1669T>G		intron	N/A	ENSP00000357042.2
	NCSTN	ENST00000913597.1		c.245-1669T>G		intron	N/A	ENSP00000583656.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15856 AN: 152146 Hom.: 1338 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.0923

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0900

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

GnomAD4 genome AF: 0.104 AC: 15888 AN: 152264 Hom.: 1343 Cov.: 32 AF XY: 0.103 AC XY: 7673 AN XY: 74462

African (AFR) AF: 0.233 AC: 9661 AN: 41512

American (AMR) AF: 0.0598 AC: 915 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3472

East Asian (EAS) AF: 0.0923 AC: 478 AN: 5176

South Asian (SAS) AF: 0.0869 AC: 420 AN: 4832

European-Finnish (FIN) AF: 0.0517 AC: 549 AN: 10612

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3371 AN: 68034

Other (OTH) AF: 0.0909 AC: 192 AN: 2112

Alfa AF: 0.0547 Hom.: 204

Bravo AF: 0.110

Asia WGS AF: 0.118 AC: 410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.66
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

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: rs10494342; hg19: chr1-160317120;