19-55852091-C-G

Position:

• chr19-55852091-C-G

Variant summary

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

The NM_134444.5(NLRP4):​c.11C>G​(p.Ser4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.59

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP4	NM_134444.5	c.11C>G	p.Ser4Cys	missense_variant	2/10	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1	c.11C>G	p.Ser4Cys	missense_variant	1/8		XP_016881833.1
NLRP4	XM_017026345.1	c.11C>G	p.Ser4Cys	missense_variant	1/8		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11	c.11C>G	p.Ser4Cys	missense_variant	2/10	1	NM_134444.5	ENSP00000301295.4
NLRP4	ENST00000587464.1	c.11C>G	p.Ser4Cys	missense_variant	2/3	2		ENSP00000468496.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 21, 2024

The c.11C>G (p.S4C) alteration is located in exon 2 (coding exon 1) of the NLRP4 gene. This alteration results from a C to G substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.23
MutPred		0.53		Loss of disorder (P = 0.0041);Loss of disorder (P = 0.0041);
MVP		0.78
MPC		0.30
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.21
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-56363457;