19-55857399-C-T

Position:

• chr19-55857399-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000301295.11(NLRP4):​c.281-275C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 473,986 control chromosomes in the GnomAD database, including 45,001 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (13999 hom., cov: 29)
  • Exomes 𝑓: 0.43 (31002 hom.)
• Consequence: NLRP4 ENST00000301295.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.485

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP4	NM_134444.5	c.281-275C>T		intron_variant		ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1	c.281-275C>T		intron_variant			XP_016881833.1
NLRP4	XM_017026345.1	c.281-275C>T		intron_variant			XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11	c.281-275C>T		intron_variant		1	NM_134444.5	ENSP00000301295	P1
NLRP4	ENST00000587464.1	c.281-275C>T		intron_variant		2		ENSP00000468496
NLRP4	ENST00000587891.5			upstream_gene_variant		2		ENSP00000465463

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64191 AN: 150078 Hom.: 13994 Cov.: 29

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.355

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.401

GnomAD4 exome AF: 0.428 AC: 138596 AN: 323788 Hom.: 31002 Cov.: 0 AF XY: 0.429 AC XY: 71164 AN XY: 166024

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.672

Gnomad4 SAS exome AF: 0.549

Gnomad4 FIN exome AF: 0.469

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.426

GnomAD4 genome AF: 0.428 AC: 64224 AN: 150198 Hom.: 13999 Cov.: 29 AF XY: 0.435 AC XY: 31822 AN XY: 73222

Gnomad4 AFR AF: 0.441

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.560

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.403

Alfa AF: 0.382 Hom.: 8727

Bravo AF: 0.425

Asia WGS AF: 0.581 AC: 2019 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.2
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs381809; hg19: chr19-56368765;