chr17-5514829-C-G

Variant names:

• chr17-5514829-C-G
• NM_033004.4:c.4347G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_033004.4(NLRP1):​c.4347G>C​(p.Lys1449Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 32)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.475

Genes affected

NLRP1 (HGNC:14374): (NLR family pyrin domain containing 1) This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a mutagenesis_site Does not affect formation of an inflammasome filament together with PYCARD/ASC. (size 0) in uniprot entity NLRP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2767598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.4347G>C	p.Lys1449Asn	missense_variant	Exon 17 of 17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.4347G>C	p.Lys1449Asn	missense_variant	Exon 17 of 17	1	NM_033004.4	ENSP00000460475.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74412

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;.;T;.;.;.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.65	.;.;.;.;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	.;.;.;N;.;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.079	.;.;.;T;.;.;.;T
Sift4G	Uncertain	0.049	.;D;T;T;D;T;T;D
Polyphen		0.89	P;P;P;P;P;P;P;P
Vest4		0.27, 0.35, 0.24, 0.33, 0.31, 0.40, 0.26
MutPred		0.52		.;.;Loss of methylation at K1449 (P = 0.015);.;.;.;Loss of methylation at K1449 (P = 0.015);.;
MVP		0.26
MPC		0.79
ClinPred		0.87	D
GERP RS		-0.88
Varity_R		0.35
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-5418149;