rs379327

Positions:

• chr19-55858800-C-G
• chr19-55858800-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_134444.5(NLRP4):​c.1407C>G​(p.His469Gln) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP4 NM_134444.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23284975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP4	NM_134444.5	c.1407C>G	p.His469Gln	missense_variant	3/10	ENST00000301295.11
NLRP4	XM_017026344.1	c.1407C>G	p.His469Gln	missense_variant	2/8
NLRP4	XM_017026345.1	c.1407C>G	p.His469Gln	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP4	ENST00000301295.11	c.1407C>G	p.His469Gln	missense_variant	3/10	1	NM_134444.5	P1
NLRP4	ENST00000589437.1	c.105C>G	p.His35Gln	missense_variant	1/7	1
NLRP4	ENST00000587891.5	c.1182C>G	p.His394Gln	missense_variant	1/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.29
Sift	Benign	0.29	T;.
Sift4G	Benign	0.25	T;T
Polyphen		0.99	D;D
Vest4		0.12
MutPred		0.36		Loss of catalytic residue at K467 (P = 0.0489);.;
MVP		0.81
MPC		0.095
ClinPred		0.29	T
GERP RS		0.63
Varity_R		0.14
gMVP		0.048

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

Other links and lift over

dbSNP: rs379327; hg19: chr19-56370166;