rs760120881

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_144687.4(NLRP12):​c.2750C>T​(p.Thr917Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

NLRP12
NM_144687.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.840
Variant links:
Genes affected
NLRP12 (HGNC:22938): (NLR family pyrin domain containing 12) This gene encodes a member of the CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminus leucine-rich repeat region, functions as an attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20786026).
BS2
High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NLRP12NM_144687.4 linkuse as main transcriptc.2750C>T p.Thr917Ile missense_variant 7/10 ENST00000324134.11 NP_653288.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NLRP12ENST00000324134.11 linkuse as main transcriptc.2750C>T p.Thr917Ile missense_variant 7/101 NM_144687.4 ENSP00000319377 P4P59046-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151942
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250626
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135544
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1461846
Hom.:
0
Cov.:
35
AF XY:
0.0000289
AC XY:
21
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151942
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
74192
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 20, 2023In 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 424097). This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. This variant is present in population databases (rs760120881, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 917 of the NLRP12 protein (p.Thr917Ile). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 09, 2017The T917I variant in the NLRP12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T917I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T917I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T917I as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T;.;.;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.32
T;T;T;T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
2.0
M;M;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-2.9
D;N;D;N
REVEL
Benign
0.093
Sift
Benign
0.11
T;T;T;T
Sift4G
Uncertain
0.040
D;T;D;T
Polyphen
0.86
P;.;.;.
Vest4
0.27
MVP
0.57
MPC
0.22
ClinPred
0.49
T
GERP RS
-2.5
Varity_R
0.054
gMVP
0.57

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: rs760120881; hg19: chr19-54304487; API