rs397514692

Variant names:

• chr17-5583728-A-G
• rs397514692
• NM_033004.4:c.230T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/21 in silico tools predict 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
• Publications: 15 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.

• 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 rank	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.230T>C	p.Met77Thr	missense_variant	Exon 1 of 17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.230T>C	p.Met77Thr	missense_variant	Exon 1 of 17	1	NM_033004.4	ENSP00000460475.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00110 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

Apr 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		0.71
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
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.84
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs397514692; hg19: chr17-5487048;