rs146932154

chr17-5521756-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033004.4(NLRP1):c.3551T>C(p.Met1184Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,612,142 control chromosomes in the GnomAD database, including 1,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1184A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.020 (240 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1481 hom.)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.90

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]

LOC124903902 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015281439).
• BP6: Variant 17-5521756-A-G is Benign according to our data. Variant chr17-5521756-A-G is described in ClinVar as [Benign]. Clinvar id is 403239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP1	NM_033004.4	c.3551T>C	p.Met1184Thr	missense_variant	13/17	ENST00000572272.6
LOC124903902	XR_007065590.1	n.250+3671A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP1	ENST00000572272.6	c.3551T>C	p.Met1184Thr	missense_variant	13/17	1	NM_033004.4	P2

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3034 AN: 152190 Hom.: 239 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0383 AC: 9583 AN: 250332 Hom.: 1240 AF XY: 0.0296 AC XY: 4005 AN XY: 135334

Gnomad AFR exome AF: 0.00390

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00445

Gnomad FIN exome AF: 0.000741

Gnomad NFE exome AF: 0.00588

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0125 AC: 18213 AN: 1459834 Hom.: 1481 Cov.: 32 AF XY: 0.0111 AC XY: 8088 AN XY: 726184

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00443

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00923

GnomAD4 genome AF: 0.0200 AC: 3042 AN: 152308 Hom.: 240 Cov.: 32 AF XY: 0.0223 AC XY: 1664 AN XY: 74482

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.00695 Hom.: 28

Bravo AF: 0.0315

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.0284 AC: 3447

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00605

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	18
Dann	Benign	0.93
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.10	N
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.71	N;.;.;N;.;N;.;.;.;N
REVEL	Benign	0.042
Sift	Uncertain	0.0030	D;.;.;D;.;D;.;.;.;D
Sift4G	Uncertain	0.012	D;D;.;D;D;D;D;D;D;D
Polyphen		0.0, 0.0010	.;.;B;B;B;B;B;B;B;B
Vest4		0.086
MPC		0.24
ClinPred		0.0078	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.53

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: rs146932154; hg19: chr17-5425076; COSMIC: COSV52559162; COSMIC: COSV52559162;