rs199694056

Variant names:

• chr1-160343457-C-A
• rs199694056
• NM_015331.3:c.61C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-160343457-C-A
• chr1-160343457-C-G
• chr1-160343457-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001290184.2(NCSTN):​c.-139C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: NCSTN NM_001290184.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.371
• Publications: 1 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]

COPA (HGNC:2230): (COPI coat complex subunit alpha) In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs). Seven coat proteins have been identified, and they represent subunits of a complex known as coatomer. The subunits are designated alpha-COP, beta-COP, beta-prime-COP, gamma-COP, delta-COP, epsilon-COP, and zeta-COP. The alpha-COP, encoded by COPA, shares high sequence similarity with RET1P, the alpha subunit of the coatomer complex in yeast. Also, the N-terminal 25 amino acids of alpha-COP encode the bioactive peptide, xenin, which stimulates exocrine pancreatic secretion and may act as a gastrointestinal hormone. Alternative splicing results in multiple splice forms encoding distinct isoforms. [provided by RefSeq, Jul 2008]

COPA Gene-Disease associations (from GenCC):

• autoimmune interstitial lung disease-arthritis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30008388).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290184.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	NM_015331.3	MANE Select	c.61C>A	p.Leu21Met	missense	Exon 1 of 17	NP_056146.1	Q92542-1
	NCSTN	NM_001290184.2		c.-139C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001277113.1	Q92542-2
	NCSTN	NM_001349729.2		c.61C>A	p.Leu21Met	missense	Exon 1 of 16	NP_001336658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.61C>A	p.Leu21Met	missense	Exon 1 of 17	ENSP00000294785.5	Q92542-1
	NCSTN	ENST00000368063.6	TSL:1	n.61C>A		non_coding_transcript_exon	Exon 1 of 18	ENSP00000357042.2	A0A2U3TZL9
	NCSTN	ENST00000913597.1		c.61C>A	p.Leu21Met	missense	Exon 1 of 18	ENSP00000583656.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.37
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.37
Sift	Benign	0.11	T
Sift4G	Uncertain	0.050	T
Polyphen		0.91	P
Vest4		0.45
MutPred		0.47		Gain of MoRF binding (P = 0.0851)
MVP		0.73
MPC		0.11
ClinPred		0.56	D
GERP RS		0.042
PromoterAI		-0.074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.58
Mutation Taster		=93/7	polymorphism

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: rs199694056; hg19: chr1-160313247;