19-55857777-G-T

Position:

chr19-55857777-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_134444.5(NLRP4):c.384G>T(p.Lys128Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,096 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

NLRP4
NM_134444.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02080211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NLRP4	NM_134444.5 linkuse as main transcript	c.384G>T	p.Lys128Asn	missense_variant	3/10	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1 linkuse as main transcript	c.384G>T	p.Lys128Asn	missense_variant	2/8		XP_016881833.1
NLRP4	XM_017026345.1 linkuse as main transcript	c.384G>T	p.Lys128Asn	missense_variant	2/8		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NLRP4	ENST00000301295.11 linkuse as main transcript	c.384G>T	p.Lys128Asn	missense_variant	3/10	1	NM_134444.5	ENSP00000301295.4	Q96MN2-1
NLRP4	ENST00000587891.5 linkuse as main transcript	c.159G>T	p.Lys53Asn	missense_variant	1/8	2		ENSP00000465463.1	Q96MN2-3
NLRP4	ENST00000587464.1 linkuse as main transcript	c.384G>T	p.Lys128Asn	missense_variant	3/3	2		ENSP00000468496.1	K7ES09

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000867

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000434

AC:

109

AN:

251410

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00137

AC:

2005

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

912

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00174

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000447

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000867

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000871

Hom.:

Bravo

AF:

0.000502

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.384G>T (p.K128N) alteration is located in exon 3 (coding exon 2) of the NLRP4 gene. This alteration results from a G to T substitution at nucleotide position 384, causing the lysine (K) at amino acid position 128 to be replaced by an asparagine (N). 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

0.25

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.39

DANN

Benign

0.84

DEOGEN2

Benign

0.0068

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.39

T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.14

N;.;.

REVEL

Benign

0.19

Sift

Benign

0.040

D;.;.

Sift4G

Uncertain

0.057

T;T;T

Polyphen

0.70

P;.;P

Vest4

0.084

MutPred

0.31

Loss of ubiquitination at K128 (P = 0.0087);Loss of ubiquitination at K128 (P = 0.0087);.;

MVP

0.37

MPC

0.048

ClinPred

0.038

GERP RS

-5.5

Varity_R

0.040

gMVP

0.066

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over