rs381809

Variant names:

• chr19-55857399-C-T
• rs381809
• NM_134444.5:c.281-275C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_134444.5(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 NM_134444.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.485
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NLRP4	NM_134444.5	c.281-275C>T		intron_variant	Intron 2 of 9	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1	c.281-275C>T		intron_variant	Intron 1 of 7		XP_016881833.1
NLRP4	XM_017026345.1	c.281-275C>T		intron_variant	Intron 1 of 7		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11	c.281-275C>T		intron_variant	Intron 2 of 9	1	NM_134444.5	ENSP00000301295.4
NLRP4	ENST00000587464.1	c.281-275C>T		intron_variant	Intron 2 of 2	2		ENSP00000468496.1
NLRP4	ENST00000587891.5	c.-220C>T		upstream_gene_variant		2		ENSP00000465463.1

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

African (AFR) AF: 0.432 AC: 4186 AN: 9700

American (AMR) AF: 0.460 AC: 5172 AN: 11236

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 4135 AN: 11036

East Asian (EAS) AF: 0.672 AC: 17500 AN: 26038

South Asian (SAS) AF: 0.549 AC: 8711 AN: 15878

European-Finnish (FIN) AF: 0.469 AC: 10987 AN: 23442

Middle Eastern (MID) AF: 0.385 AC: 597 AN: 1552

European-Non Finnish (NFE) AF: 0.384 AC: 78721 AN: 204744

Other (OTH) AF: 0.426 AC: 8587 AN: 20162

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

African (AFR) AF: 0.441 AC: 17970 AN: 40712

American (AMR) AF: 0.455 AC: 6824 AN: 14994

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3470

East Asian (EAS) AF: 0.676 AC: 3435 AN: 5080

South Asian (SAS) AF: 0.560 AC: 2664 AN: 4754

European-Finnish (FIN) AF: 0.468 AC: 4787 AN: 10236

Middle Eastern (MID) AF: 0.333 AC: 96 AN: 288

European-Non Finnish (NFE) AF: 0.386 AC: 26132 AN: 67690

Other (OTH) AF: 0.403 AC: 836 AN: 2076

Alfa AF: 0.388 Hom.: 11631

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
PhyloP100		-0.48
PromoterAI		0.11	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs381809; hg19: chr19-56368765;