19-55954908-C-A

Position:

• chr19-55954908-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_176811.2(NLRP8):​c.850C>A​(p.Leu284Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L284F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP8 NM_176811.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.05

Genes affected

NLRP8 (HGNC:22940): (NLR family pyrin domain containing 8) This gene encodes a member of the nucleotide-binding oligomerization domain/ leucine rich repeat/ pyrin domain containing (NLRP) subfamily, which belongs to the Nod-like receptor family of proteins. NLRP genes play roles in the mammalian innate immune system through inflammasome formation and activation of caspases. In addition, NLRP genes have been found to function during mammalian reproduction. Consistent with a function during human preimplantation development, this gene is expressed at high levels in oocytes with decreased levels in embryos. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08098215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP8	NM_176811.2	c.850C>A	p.Leu284Ile	missense_variant	3/10	ENST00000291971.7
NLRP8	NM_001317000.1	c.850C>A	p.Leu284Ile	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP8	ENST00000291971.7	c.850C>A	p.Leu284Ile	missense_variant	3/10	1	NM_176811.2	P2
NLRP8	ENST00000590542.1	c.850C>A	p.Leu284Ile	missense_variant	3/10	1		A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Human Evolutionary Genetics, Institut Pasteur

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.9
DANN	Benign	0.51
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.47	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.94	N;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.083	B;P
Vest4		0.22
MutPred		0.52		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.31
MPC		0.17
ClinPred		0.14	T
GERP RS		-0.39
Varity_R		0.072
gMVP		0.083

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: rs199475836; hg19: chr19-56466274;