chr19-55792364-T-A

Variant names:

• chr19-55792364-T-A
• rs1025272758
• NM_001394894.2:c.2450A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001394894.2(NLRP11):​c.2450A>T​(p.Asn817Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NLRP11 NM_001394894.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.987
• Publications: 1 publications found

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]

NLRP11 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394894.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP11	NM_001394894.2	MANE Select	c.2450A>T	p.Asn817Ile	missense	Exon 7 of 10	NP_001381823.1	P59045-1
	NLRP11	NM_145007.5		c.2450A>T	p.Asn817Ile	missense	Exon 9 of 12	NP_659444.2	P59045-1
	NLRP11	NM_001385451.2		c.2288A>T	p.Asn763Ile	missense	Exon 8 of 11	NP_001372380.1	P59045-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP11	ENST00000589093.6	TSL:1 MANE Select	c.2450A>T	p.Asn817Ile	missense	Exon 7 of 10	ENSP00000466285.1	P59045-1
	NLRP11	ENST00000592953.5	TSL:1	c.2153A>T	p.Asn718Ile	missense	Exon 6 of 9	ENSP00000468196.1	P59045-3
	NLRP11	ENST00000590409.5	TSL:1	n.*264A>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000466582.1	K7EMN8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.99
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.55		Gain of catalytic residue at N817 (P = 0.0465)
MVP		0.68
ClinPred		0.65	D
GERP RS		1.1
Varity_R		0.14
gMVP		0.31
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1025272758; hg19: chr19-56303730; COSMIC: COSV64089192; COSMIC: COSV64089192;