rs397514692

Positions:

• chr17-5583728-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_033004.4(NLRP1):​c.230T>C​(p.Met77Thr) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.712

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-5583728-A-G is Pathogenic according to our data. Variant chr17-5583728-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 50316.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23050794). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.230T>C	p.Met77Thr	missense_variant	1/17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.230T>C	p.Met77Thr	missense_variant	1/17	1	NM_033004.4	ENSP00000460475	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00422 Hom.: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.23	.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.72	.;T;.;.;.;.;T;T;T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D;.;.;D;.;D;.;.;.;D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;.;.;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0090	D;D;.;D;D;D;D;D;D;D
Polyphen		0.19, 0.23	.;.;B;B;B;B;B;B;B;B
Vest4		0.41
MutPred		0.60		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);
MVP		0.49
MPC		0.61
ClinPred		0.52	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.84

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: rs397514692; hg19: chr17-5487048;