chr17-5514773-A-G

Variant names:

• chr17-5514773-A-G
• rs201882873
• NM_033004.4:c.4403T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033004.4(NLRP1):​c.4403T>C​(p.Leu1468Pro) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1468H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156
• Publications: 1 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):

• autoinflammation with arthritis and dyskeratosis

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

  Inheritance: SD, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004866332).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033004.4. 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
	NLRP1	NM_033004.4	MANE Select	c.4403T>C	p.Leu1468Pro	missense	Exon 17 of 17	NP_127497.1	Q9C000-1
	NLRP1	NM_033006.4		c.4313T>C	p.Leu1438Pro	missense	Exon 16 of 16	NP_127499.1	Q9C000-4
	NLRP1	NM_014922.5		c.4271T>C	p.Leu1424Pro	missense	Exon 16 of 16	NP_055737.1	Q9C000-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP1	ENST00000572272.6	TSL:1 MANE Select	c.4403T>C	p.Leu1468Pro	missense	Exon 17 of 17	ENSP00000460475.1	Q9C000-1
	NLRP1	ENST00000354411.8	TSL:1	c.4313T>C	p.Leu1438Pro	missense	Exon 16 of 16	ENSP00000346390.3	Q9C000-4
	NLRP1	ENST00000269280.9	TSL:1	c.4271T>C	p.Leu1424Pro	missense	Exon 17 of 17	ENSP00000269280.4	Q9C000-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00126 AC: 308 AN: 245386 AF XY: 0.000739

Gnomad AFR exome AF: 0.00660

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.000847

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000273 AC: 398 AN: 1460398 Hom.: 0 Cov.: 32 AF XY: 0.000279 AC XY: 203 AN XY: 726498

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00644 AC: 338 AN: 52496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111676

Other (OTH) AF: 0.000448 AC: 27 AN: 60242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00303 AC: 366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.73	T
PhyloP100		-0.16
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.073	B
Vest4		0.20
MVP		0.24
MPC		0.36
ClinPred		0.0036	T
GERP RS		-6.1
Varity_R		0.094
gMVP		0.46

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: rs201882873; hg19: chr17-5418093;