Genetic Variant NLRP1:p.Pro1214Arg (chr17-5521666-G-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_033004.4(NLRP1):c.3641C>G(p.Pro1214Arg) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1214P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NLRP1
NM_033004.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.267

Publications

23 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
autoinflammation with arthritis and dyskeratosis
Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

NLRP1 links:

LOC124903902 (HGNC:):

LOC124903902 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-5521666-G-C is Pathogenic according to our data. Variant chr17-5521666-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 393320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.31169415). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033004.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRP1	NM_033004.4	MANE Select	c.3641C>G	p.Pro1214Arg	missense	Exon 13 of 17	NP_127497.1	Q9C000-1
NLRP1	NM_033006.4		c.3551C>G	p.Pro1184Arg	missense	Exon 12 of 16	NP_127499.1	Q9C000-4
NLRP1	NM_014922.5		c.3641C>G	p.Pro1214Arg	missense	Exon 13 of 16	NP_055737.1	Q9C000-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRP1	ENST00000572272.6	TSL:1 MANE Select	c.3641C>G	p.Pro1214Arg	missense	Exon 13 of 17	ENSP00000460475.1	Q9C000-1
NLRP1	ENST00000354411.8	TSL:1	c.3551C>G	p.Pro1184Arg	missense	Exon 12 of 16	ENSP00000346390.3	Q9C000-4
NLRP1	ENST00000269280.9	TSL:1	c.3641C>G	p.Pro1214Arg	missense	Exon 14 of 17	ENSP00000269280.4	Q9C000-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoinflammation with arthritis and dyskeratosis (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

Eigen

Benign

-0.041

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.058

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0013

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.1

PhyloP100

0.27

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.070

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.53

MutPred

0.63

Gain of MoRF binding (P = 0.023)

MVP

0.63

MPC

0.83

ClinPred

0.99

GERP RS

0.64

Varity_R

0.58

gMVP

0.73

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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