Genetic Variant NCSTN:p.Ala315Val (chr1-160352154-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_015331.3(NCSTN):c.944C>T(p.Ala315Val) variant causes a missense 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. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

NCSTN
NM_015331.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.0830

Publications

1 publications found

Variant links:

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

NCSTN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-160352154-C-T is Pathogenic according to our data. Variant chr1-160352154-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 559854.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCSTN	NM_015331.3	MANE Select	c.944C>T	p.Ala315Val	missense	Exon 8 of 17	NP_056146.1	Q92542-1
NCSTN	NM_001290184.2		c.884C>T	p.Ala295Val	missense	Exon 9 of 18	NP_001277113.1	Q92542-2
NCSTN	NM_001349729.2		c.944C>T	p.Ala315Val	missense	Exon 8 of 16	NP_001336658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.944C>T	p.Ala315Val	missense	Exon 8 of 17	ENSP00000294785.5	Q92542-1
NCSTN	ENST00000368063.6	TSL:1	n.*873C>T		non_coding_transcript_exon	Exon 9 of 18	ENSP00000357042.2	A0A2U3TZL9
NCSTN	ENST00000368063.6	TSL:1	n.*873C>T		3_prime_UTR	Exon 9 of 18	ENSP00000357042.2	A0A2U3TZL9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Acne inversa, familial, 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.83

M_CAP

Benign

0.018

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

0.083

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.55

REVEL

Benign

0.042

Sift

Benign

0.15

Sift4G

Benign

0.41

Polyphen

0.30

Vest4

0.16

MutPred

0.48

Loss of helix (P = 0.0626)

MVP

0.69

MPC

0.96

ClinPred

0.11

GERP RS

3.2

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.69

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.97

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over