Genetic Variant NLRP1:c.-355+3645T>C (chr17-5615686-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000576905.6(NLRP1):c.-355+3645T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 152,048 control chromosomes in the GnomAD database, including 13,284 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.41 ( 13284 hom., cov: 32)

Consequence

NLRP1
ENST00000576905.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.23

Publications

53 publications found

Variant links:

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

NLRP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000576905.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NLRP1	ENST00000576905.6	TSL:4	c.-355+3645T>C	intron	N/A	ENSP00000458303.2	Q9C000-2
NLRP1	ENST00000572143.2	TSL:4	n.-544+3645T>C	intron	N/A	ENSP00000514476.1	A0A8V8TNH7
NLRP1	ENST00000699639.1		n.84+3645T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.412

AC:

62532

AN:

151928

Hom.:

13259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.347

Gnomad AMI

AF:

0.584

Gnomad AMR

AF:

0.432

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.439

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.456

Gnomad OTH

AF:

0.412

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.412

AC:

62612

AN:

152048

Hom.:

13284

Cov.:

AF XY:

0.411

AC XY:

30537

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.347

AC:

14409

AN:

41478

American (AMR)

AF:

0.432

AC:

6608

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

1601

AN:

3472

East Asian (EAS)

AF:

0.179

AC:

923

AN:

5170

South Asian (SAS)

AF:

0.404

AC:

1948

AN:

4826

European-Finnish (FIN)

AF:

0.439

AC:

4625

AN:

10542

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.456

AC:

30962

AN:

67960

Other (OTH)

AF:

0.419

AC:

882

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1861

3722

5584

7445

9306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.424

Hom.:

1755

Bravo

AF:

0.408

Asia WGS

AF:

0.344

AC:

1197

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over