19-55796093-G-T

Position:

• chr19-55796093-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001394894.2(NLRP11):​c.2329C>A​(p.Leu777Ile) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP11 NM_001394894.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.457

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37469324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP11	NM_001394894.2	c.2329C>A	p.Leu777Ile	missense_variant	6/10	ENST00000589093.6	NP_001381823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP11	ENST00000589093.6	c.2329C>A	p.Leu777Ile	missense_variant	6/10	1	NM_001394894.2	ENSP00000466285	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

The c.2329C>A (p.L777I) alteration is located in exon 8 (coding exon 5) of the NLRP11 gene. This alteration results from a C to A substitution at nucleotide position 2329, causing the leucine (L) at amino acid position 777 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.41	T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.9	.;.;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.40
MutPred		0.59		.;.;Loss of sheet (P = 0.1907);
MVP		0.75
ClinPred		0.61	D
GERP RS		1.5
Varity_R		0.11
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-56307459;