Genetic Variant NLRP1:p.Ala54Thr (chr17-5583798-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_033004.4(NLRP1):c.160G>A(p.Ala54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NLRP1
NM_033004.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.55

Publications

12 publications found

Variant links:

Genes affected

NLRP1 (HGNC:14374): (NLR family pyrin domain containing 1) This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

NLRP1 Gene-Disease associations (from GenCC):

corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome
Inheritance: AD, SD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
autoinflammation with arthritis and dyskeratosis
Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

NLRP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-5583798-C-T is Pathogenic according to our data. Variant chr17-5583798-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375413.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4 link	c.160G>A	p.Ala54Thr	missense_variant	Exon 1 of 17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6 link	c.160G>A	p.Ala54Thr	missense_variant	Exon 1 of 17	1	NM_033004.4	ENSP00000460475.1		Q9C000-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1405058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693658

African (AFR)

AF:

0.00

AC:

AN:

31974

American (AMR)

AF:

0.00

AC:

AN:

36590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25304

East Asian (EAS)

AF:

0.00

AC:

AN:

36206

South Asian (SAS)

AF:

0.00

AC:

AN:

79836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081742

Other (OTH)

AF:

0.00

AC:

AN:

58200

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

Pathogenic:1

Sep 30, 2019

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.022

.;.;.;.;T;.;.;.;T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.049

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.73

.;T;.;.;.;.;T;T;T;T

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.79

PhyloP100

1.5

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.0

N;.;.;N;.;N;.;.;.;N

REVEL

Benign

0.27

Sift

Uncertain

0.0030

D;.;.;D;.;D;.;.;.;D

Sift4G

Uncertain

0.014

D;D;.;D;D;D;D;D;D;D

Polyphen

0.94, 0.99, 0.99

.;.;P;P;D;D;D;D;D;P

Vest4

0.27

MutPred

0.69

Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);

MVP

0.82

MPC

0.77

ClinPred

0.89

GERP RS

2.5

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.68

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over