19-55858800-C-T

Variant names:

• chr19-55858800-C-T
• rs379327
• NM_134444.5:c.1407C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_134444.5(NLRP4):​c.1407C>T​(p.His469His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,904 control chromosomes in the GnomAD database, including 12,871 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 0.10 (1019 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11852 hom.)
• Consequence: NLRP4 NM_134444.5 synonymous
• 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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP4	NM_134444.5	c.1407C>T	p.His469His	synonymous_variant	Exon 3 of 10	ENST00000301295.11	NP_604393.2
NLRP4	XM_017026344.1	c.1407C>T	p.His469His	synonymous_variant	Exon 2 of 8		XP_016881833.1
NLRP4	XM_017026345.1	c.1407C>T	p.His469His	synonymous_variant	Exon 2 of 8		XP_016881834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP4	ENST00000301295.11	c.1407C>T	p.His469His	synonymous_variant	Exon 3 of 10	1	NM_134444.5	ENSP00000301295.4
NLRP4	ENST00000589437.1	c.102C>T	p.His34His	synonymous_variant	Exon 1 of 7	1		ENSP00000468754.1
NLRP4	ENST00000587891.5	c.1182C>T	p.His394His	synonymous_variant	Exon 1 of 8	2		ENSP00000465463.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15282 AN: 152120 Hom.: 1018 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.131 AC: 32873 AN: 251470 Hom.: 2601 AF XY: 0.126 AC XY: 17169 AN XY: 135906

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.0932

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.123 AC: 179395 AN: 1461666 Hom.: 11852 Cov.: 35 AF XY: 0.121 AC XY: 88306 AN XY: 727156

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.0932

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.100 AC: 15285 AN: 152238 Hom.: 1019 Cov.: 32 AF XY: 0.100 AC XY: 7451 AN XY: 74424

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.0905

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.116

Alfa AF: 0.120 Hom.: 1913

Bravo AF: 0.107

Asia WGS AF: 0.110 AC: 383 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.124

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.47

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; COSMIC: COSV56713788; COSMIC: COSV56713788;