rs1057519492

Positions:

• chr17-5583798-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_033004.4(NLRP1):​c.160G>A​(p.Ala54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.55

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.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-5583798-C-T is Pathogenic according to our data. Variant chr17-5583798-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375413.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP1	NM_033004.4	c.160G>A	p.Ala54Thr	missense_variant	1/17	ENST00000572272.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP1	ENST00000572272.6	c.160G>A	p.Ala54Thr	missense_variant	1/17	1	NM_033004.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 693658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Pathogenic	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.97	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;.;.;N;.;N;.;.;.;N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;.;.;D;.;D;.;.;.;D
Sift4G	Uncertain	0.014	D;D;.;D;D;D;D;D;D;D
Polyphen		0.94, 0.99, 0.99	.;.;P;P;D;D;D;D;D;P
Vest4		0.27
MutPred		0.69		Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);Gain of glycosylation at A54 (P = 0.0871);
MVP		0.82
MPC		0.77
ClinPred		0.89	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1057519492; hg19: chr17-5487118;