rs12461110

Positions:

• chr19-55809297-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001394894.2(NLRP11):​c.1313C>T​(p.Pro438Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,138 control chromosomes in the GnomAD database, including 94,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6490 hom., cov: 32)
  • Exomes 𝑓: 0.34 (88133 hom.)
• Consequence: NLRP11 NM_001394894.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21

Genes affected

NLRP11 (HGNC:22945): (NLR family pyrin domain containing 11) This gene is a member of the the NOD-like receptor protein (NLRP) gene family and encodes a protein with an N-terminal pyrin death (PYD) domain and nucleoside triphosphate hydrolase (NACHT) domain and a C-terminal leucine-rich repeats (LRR) region. This gene has been shown to regulate caspases in the proinflammatory signal transduction pathway and, based on studies of other members of the NLRP gene family with similar domain structure, is predicted to form part of the multiprotein inflammasome complex. Alternative splicing produces multiple transcript variants encoding distince isoforms. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031175911).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP11	NM_001394894.2	c.1313C>T	p.Pro438Leu	missense_variant	3/10	ENST00000589093.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP11	ENST00000589093.6	c.1313C>T	p.Pro438Leu	missense_variant	3/10	1	NM_001394894.2	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40631 AN: 151790 Hom.: 6490 Cov.: 32

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.281

GnomAD3 exomes AF: 0.321 AC: 80523 AN: 251080 Hom.: 13618 AF XY: 0.323 AC XY: 43819 AN XY: 135726

Gnomad AFR exome AF: 0.0686

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.305

Gnomad SAS exome AF: 0.300

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.343 AC: 500856 AN: 1461228 Hom.: 88133 Cov.: 38 AF XY: 0.342 AC XY: 248540 AN XY: 726888

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.376

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.271

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.361

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.268 AC: 40640 AN: 151910 Hom.: 6490 Cov.: 32 AF XY: 0.267 AC XY: 19832 AN XY: 74252

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.302

Gnomad4 NFE AF: 0.352

Gnomad4 OTH AF: 0.283

Alfa AF: 0.329 Hom.: 15962

Bravo AF: 0.264

TwinsUK AF: 0.368 AC: 1364

ALSPAC AF: 0.358 AC: 1379

ESP6500AA AF: 0.0828 AC: 365

ESP6500EA AF: 0.343 AC: 2954

ExAC AF: 0.316 AC: 38321

Asia WGS AF: 0.268 AC: 931 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.341

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.40
DANN	Benign	0.87
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.99	D;.;P
Vest4		0.068
ClinPred		0.0078	T
GERP RS		-4.4
Varity_R		0.029
gMVP		0.50

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

Other links and lift over

dbSNP: rs12461110; hg19: chr19-56320663; COSMIC: COSV64086315; COSMIC: COSV64086315;