Genetic Variant ENST00000574512.1:n.821-5741T>G (chr17-5511718-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000574512.1(NLRP1):n.821-5741T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 142,906 control chromosomes in the GnomAD database, including 3,623 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 0.17 ( 3623 hom., cov: 31)

Consequence

NLRP1
ENST00000574512.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.42

Publications

4 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: 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

NLRP1 links:

LOC101928044 (HGNC:):

LOC101928044 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=-1.09).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_001033053.3 link	c.4069+6028T>G		intron_variant	Intron 15 of 15		NP_001028225.1
LOC101928044	XM_047437231.1 link	c.*322T>G		downstream_gene_variant			XP_047293187.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NLRP1	ENST00000574512.1 link	n.821-5741T>G	intron_variant	Intron 1 of 1	1
NLRP1	ENST00000699613.1 link	c.4102+3755T>G	intron_variant	Intron 16 of 16		ENSP00000514477.1	A0A8V8TNP3
NLRP1	ENST00000262467.11 link	c.4069+6028T>G	intron_variant	Intron 15 of 15	5	ENSP00000262467.5	Q9C000-5

Frequencies

GnomAD3 genomes

AF:

0.165

AC:

23545

AN:

142808

Hom.:

3605

Cov.:

show subpopulations

Gnomad AFR

AF:

0.428

Gnomad AMI

AF:

0.0302

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0826

Gnomad EAS

AF:

0.0784

Gnomad SAS

AF:

0.0400

Gnomad FIN

AF:

0.0452

Gnomad MID

AF:

0.107

Gnomad NFE

AF:

0.0598

Gnomad OTH

AF:

0.158

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

GnomAD4 genome

AF:

0.165

AC:

23602

AN:

142906

Hom.:

3623

Cov.:

AF XY:

0.161

AC XY:

11149

AN XY:

69110

show subpopulations

African (AFR)

AF:

0.429

AC:

16598

AN:

38726

American (AMR)

AF:

0.105

AC:

1515

AN:

14366

Ashkenazi Jewish (ASJ)

AF:

0.0826

AC:

282

AN:

3414

East Asian (EAS)

AF:

0.0784

AC:

315

AN:

4016

South Asian (SAS)

AF:

0.0393

AC:

166

AN:

4224

European-Finnish (FIN)

AF:

0.0452

AC:

416

AN:

9210

Middle Eastern (MID)

AF:

0.115

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0599

AC:

3940

AN:

65826

Other (OTH)

AF:

0.157

AC:

312

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

805

1611

2416

3222

4027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.117

Hom.:

387

Bravo

AF:

0.173

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.43

(source)

DANN

Benign

0.28

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over