dbSNP rs759611908: NLRP4:p.Phe23Leu (chr19-55852149-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_134444.5(NLRP4):c.69C>A(p.Phe23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NLRP4
NM_134444.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.122

Variant links:

Genes affected

NLRP4 (HGNC:22943): (NLR family pyrin domain containing 4) The protein encoded by this gene is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family, and is predicted to contain an N-terminal pyrin effector domain (PYD), a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). This gene product has a demonstrated role as a negative regulator of autophagy and type I interferon signaling pathways as a result of protein interactions with its NACHT domain. The PYD domain has also been shown to be important in the inhibition of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells). [provided by RefSeq, Dec 2016]

NLRP4 links:

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ACMG classification

Classification made for transcript

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=0.20300272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NLRP4	NM_134444.5 link	c.69C>A	p.Phe23Leu	missense_variant	Exon 2 of 10	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1 link	c.69C>A	p.Phe23Leu	missense_variant	Exon 1 of 8		XP_016881833.1
NLRP4	XM_017026345.1 link	c.69C>A	p.Phe23Leu	missense_variant	Exon 1 of 8		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11 link	c.69C>A	p.Phe23Leu	missense_variant	Exon 2 of 10	1	NM_134444.5	ENSP00000301295.4		Q96MN2-1
NLRP4	ENST00000587464.1 link	c.69C>A	p.Phe23Leu	missense_variant	Exon 2 of 3	2		ENSP00000468496.1		K7ES09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455358

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723764

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.49

T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.72

N;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.5

D;.

REVEL

Benign

0.13

Sift

Benign

0.061

T;.

Sift4G

Benign

0.17

T;D

Polyphen

0.88

P;.

Vest4

0.38

MutPred

0.57

Loss of methylation at K20 (P = 0.1172);Loss of methylation at K20 (P = 0.1172);

MVP

0.39

MPC

0.29

ClinPred

0.50

GERP RS

0.92

Varity_R

0.63

gMVP

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over