19-55858800-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134444.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP4	NM_134444.5	MANE Select	c.1407C>T	p.His469His	synonymous	Exon 3 of 10	NP_604393.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP4	ENST00000301295.11	TSL:1 MANE Select	c.1407C>T	p.His469His	synonymous	Exon 3 of 10	ENSP00000301295.4
	NLRP4	ENST00000589437.1	TSL:1	c.102C>T	p.His34His	synonymous	Exon 1 of 7	ENSP00000468754.1
	NLRP4	ENST00000587891.5	TSL:2	c.1182C>T	p.His394His	synonymous	Exon 1 of 8	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

GnomAD2 exomes AF: 0.131 AC: 32873 AN: 251470 AF XY: 0.126

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 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

African (AFR) AF: 0.0199 AC: 665 AN: 33476

American (AMR) AF: 0.235 AC: 10529 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3690 AN: 26134

East Asian (EAS) AF: 0.151 AC: 6000 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8864 AN: 86256

European-Finnish (FIN) AF: 0.0932 AC: 4977 AN: 53418

Middle Eastern (MID) AF: 0.0936 AC: 540 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136956 AN: 1111802

Other (OTH) AF: 0.119 AC: 7174 AN: 60388

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

African (AFR) AF: 0.0248 AC: 1029 AN: 41564

American (AMR) AF: 0.178 AC: 2725 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3472

East Asian (EAS) AF: 0.168 AC: 869 AN: 5168

South Asian (SAS) AF: 0.115 AC: 552 AN: 4820

European-Finnish (FIN) AF: 0.0905 AC: 959 AN: 10598

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8306 AN: 68004

Other (OTH) AF: 0.116 AC: 246 AN: 2116

Alfa AF: 0.120 Hom.: 2347

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.47
PhyloP100		1.4
PromoterAI		0.066	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs379327; hg19: chr19-56370166; COSMIC: COSV56713788; COSMIC: COSV56713788;