19-55852210-T-C

Position:

• chr19-55852210-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_134444.5(NLRP4):​c.130T>C​(p.Trp44Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP4 NM_134444.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.818

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP4	NM_134444.5	c.130T>C	p.Trp44Arg	missense_variant	2/10	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1	c.130T>C	p.Trp44Arg	missense_variant	1/8		XP_016881833.1
NLRP4	XM_017026345.1	c.130T>C	p.Trp44Arg	missense_variant	1/8		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11	c.130T>C	p.Trp44Arg	missense_variant	2/10	1	NM_134444.5	ENSP00000301295.4
NLRP4	ENST00000587464.1	c.130T>C	p.Trp44Arg	missense_variant	2/3	2		ENSP00000468496.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.130T>C (p.W44R) alteration is located in exon 2 (coding exon 1) of the NLRP4 gene. This alteration results from a T to C substitution at nucleotide position 130, causing the tryptophan (W) at amino acid position 44 to be replaced by an arginine (R). 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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-11	D;.
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.31
MutPred		0.70		Gain of disorder (P = 0.0016);Gain of disorder (P = 0.0016);
MVP		0.70
MPC		0.34
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.67
gMVP		0.16

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.

Other links and lift over

hg19: chr19-56363576;