19-55788829-C-A

Variant names:

• chr19-55788829-C-A
• rs562593953
• NM_001394894.2:c.2833G>T

Variant summary

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

The NM_001394894.2(NLRP11):​c.2833G>T​(p.Asp945Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,579,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D945N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NLRP11 NM_001394894.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.172
• Publications: 4 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.2833G>T	p.Asp945Tyr	missense	Exon 9 of 10	NP_001381823.1	P59045-1
	NLRP11	NM_145007.5		c.2833G>T	p.Asp945Tyr	missense	Exon 11 of 12	NP_659444.2	P59045-1
	NLRP11	NM_001385451.2		c.2671G>T	p.Asp891Tyr	missense	Exon 10 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.2833G>T	p.Asp945Tyr	missense	Exon 9 of 10	ENSP00000466285.1	P59045-1
	NLRP11	ENST00000592953.5	TSL:1	c.2536G>T	p.Asp846Tyr	missense	Exon 8 of 9	ENSP00000468196.1	P59045-3
	NLRP11	ENST00000590409.5	TSL:1	n.*647G>T		non_coding_transcript_exon	Exon 11 of 12	ENSP00000466582.1	K7EMN8

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148680 Hom.: 0 Cov.: 32

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: 0.000219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251428 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430670 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 711310

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.00 AC: 0 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 36764

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092134

Other (OTH) AF: 0.00 AC: 0 AN: 58246

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148784 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72484

African (AFR) AF: 0.00 AC: 0 AN: 40526

American (AMR) AF: 0.00 AC: 0 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67422

Other (OTH) AF: 0.00 AC: 0 AN: 2074

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.17
PrimateAI	Benign	0.25	T
Sift4G	Uncertain	0.031	D
Polyphen		0.95	P
Vest4		0.36
MutPred		0.53		Loss of helix (P = 0.0558)
MVP		0.58
ClinPred		0.26	T
GERP RS		-4.3
Varity_R		0.093
gMVP		0.22
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -22

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

Other links and lift over

dbSNP: rs562593953; hg19: chr19-56300195;