chr17-5514863-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033004.4(NLRP1):​c.4313G>A​(p.Arg1438Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

NLRP1
NM_033004.4 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -2.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007987678).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NLRP1NM_033004.4 linkuse as main transcriptc.4313G>A p.Arg1438Gln missense_variant 17/17 ENST00000572272.6 NP_127497.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NLRP1ENST00000572272.6 linkuse as main transcriptc.4313G>A p.Arg1438Gln missense_variant 17/171 NM_033004.4 ENSP00000460475 P2Q9C000-1

Frequencies

GnomAD3 genomes
AF:
0.000460
AC:
70
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00109
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000353
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000200
AC:
50
AN:
249518
Hom.:
0
AF XY:
0.000185
AC XY:
25
AN XY:
135386
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000221
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000315
AC:
461
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.000298
AC XY:
217
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00140
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000349
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.000460
AC:
70
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.000322
AC XY:
24
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00108
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000353
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000296
Hom.:
0
Bravo
AF:
0.000518
ESP6500AA
AF:
0.000983
AC:
4
ESP6500EA
AF:
0.000359
AC:
3
ExAC
AF:
0.000248
AC:
30
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000474

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 07, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1438 of the NLRP1 protein (p.Arg1438Gln). This variant is present in population databases (rs201167590, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NLRP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 502755). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 27, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenMay 10, 2022- -
NLRP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 08, 2023The NLRP1 c.4313G>A variant is predicted to result in the amino acid substitution p.Arg1438Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-5418183-C-T), which may be too common to be an unreported disease-causing variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.68
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
4.3
DANN
Benign
0.87
DEOGEN2
Benign
0.018
.;.;T;.;.;.;T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.0060
N
LIST_S2
Benign
0.51
.;.;.;.;T;T;T;T
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.0080
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.81
.;.;.;N;.;.;.;N
REVEL
Benign
0.041
Sift
Benign
0.28
.;.;.;T;.;.;.;T
Sift4G
Benign
0.31
.;T;T;T;T;T;T;T
Polyphen
0.85
P;P;P;P;P;P;P;P
Vest4
0.064, 0.12, 0.086, 0.16, 0.083, 0.12, 0.11
MVP
0.081
MPC
0.30
ClinPred
0.0089
T
GERP RS
-10
Varity_R
0.035
gMVP
0.083

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201167590; hg19: chr17-5418183; COSMIC: COSV52564144; COSMIC: COSV52564144; API