Variant 19-55852217-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_134444.5(NLRP4):c.137A>T(p.Glu46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000435 in 1,609,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

NLRP4
NM_134444.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.330

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NLRP4	NM_134444.5 linkuse as main transcript	c.137A>T	p.Glu46Val	missense_variant	2/10	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1 linkuse as main transcript	c.137A>T	p.Glu46Val	missense_variant	1/8		XP_016881833.1
NLRP4	XM_017026345.1 linkuse as main transcript	c.137A>T	p.Glu46Val	missense_variant	1/8		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11 linkuse as main transcript	c.137A>T	p.Glu46Val	missense_variant	2/10	1	NM_134444.5	ENSP00000301295.4		Q96MN2-1
NLRP4	ENST00000587464.1 linkuse as main transcript	c.137A>T	p.Glu46Val	missense_variant	2/3	2		ENSP00000468496.1		K7ES09

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

246360

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133128

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000800

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000460

AC:

AN:

1457184

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

724772

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

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

Mar 13, 2023

The c.137A>T (p.E46V) alteration is located in exon 2 (coding exon 1) of the NLRP4 gene. This alteration results from a A to T substitution at nucleotide position 137, causing the glutamic acid (E) at amino acid position 46 to be replaced by a valine (V). 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

0.23

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;.

Eigen

Benign

0.10

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Benign

0.29

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.27

MVP

0.81

MPC

0.32

ClinPred

0.71

GERP RS

4.3

Varity_R

0.47

gMVP

0.20

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