17-5514805-C-T

Variant names:

• chr17-5514805-C-T
• rs201638843
• NM_033004.4:c.4371G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_033004.4(NLRP1):​c.4371G>A​(p.Met1457Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 0 publications found

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]

NLRP1 Gene-Disease associations (from GenCC):

• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

  Inheritance: AD, SD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• autoinflammation with arthritis and dyskeratosis

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a mutagenesis_site Does not affect ability to induce programmed cell death. (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=0.0810841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.4371G>A	p.Met1457Ile	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.4371G>A	p.Met1457Ile	missense_variant	Exon 17 of 17	1	NM_033004.4	ENSP00000460475.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.1
DANN	Benign	0.63
DEOGEN2	Benign	0.028	.;.;T;.;.;.;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.44	.;.;.;.;T;T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	.;.;.;N;.;.;.;N
REVEL	Benign	0.038
Sift	Uncertain	0.0050	.;.;.;D;.;.;.;D
Sift4G	Uncertain	0.013	.;D;D;D;D;D;D;D
Polyphen		0.50	P;P;P;P;P;P;P;P
Vest4		0.34, 0.32, 0.30, 0.41, 0.32, 0.34, 0.30
MutPred		0.45		.;.;Loss of disorder (P = 0.0753);.;.;.;Loss of disorder (P = 0.0753);.;
MVP		0.20
MPC		0.28
ClinPred		0.11	T
GERP RS		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.17

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: rs201638843; hg19: chr17-5418125; COSMIC: COSV104579765; COSMIC: COSV104579765;