chr1-160353563-A-G

Variant names:

• chr1-160353563-A-G
• rs1124379
• NM_015331.3:c.1179+326A>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.1179+326A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,247,944 control chromosomes in the GnomAD database, including 206,234 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 0.63 (31399 hom., cov: 31)
  • Exomes 𝑓: 0.56 (174835 hom.)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95163 AN: 151900 Hom.: 31349 Cov.: 31

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.615

GnomAD4 exome AF: 0.561 AC: 615005 AN: 1095926 Hom.: 174835 Cov.: 33 AF XY: 0.563 AC XY: 296064 AN XY: 526212

African (AFR) AF: 0.860 AC: 20282 AN: 23592

American (AMR) AF: 0.559 AC: 7620 AN: 13630

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 5621 AN: 12422

East Asian (EAS) AF: 0.475 AC: 8172 AN: 17218

South Asian (SAS) AF: 0.677 AC: 38253 AN: 56500

European-Finnish (FIN) AF: 0.514 AC: 6714 AN: 13066

Middle Eastern (MID) AF: 0.597 AC: 1585 AN: 2656

European-Non Finnish (NFE) AF: 0.550 AC: 503518 AN: 915586

Other (OTH) AF: 0.563 AC: 23240 AN: 41256

GnomAD4 genome AF: 0.627 AC: 95273 AN: 152018 Hom.: 31399 Cov.: 31 AF XY: 0.624 AC XY: 46330 AN XY: 74280

African (AFR) AF: 0.846 AC: 35111 AN: 41496

American (AMR) AF: 0.565 AC: 8624 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1528 AN: 3462

East Asian (EAS) AF: 0.475 AC: 2445 AN: 5146

South Asian (SAS) AF: 0.685 AC: 3307 AN: 4826

European-Finnish (FIN) AF: 0.542 AC: 5729 AN: 10562

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36466 AN: 67934

Other (OTH) AF: 0.616 AC: 1299 AN: 2110

Alfa AF: 0.582 Hom.: 21606

Bravo AF: 0.639

Asia WGS AF: 0.607 AC: 2109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.87
PhyloP100		-0.56
Mutation Taster		=100/0	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: rs1124379; hg19: chr1-160323353;