17-5583844-C-G

Variant names:

• chr17-5583844-C-G
• rs884367
• NM_033004.4:c.114G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033004.4(NLRP1):​c.114G>C​(p.Ser38Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,569,478 control chromosomes in the GnomAD database, including 37,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3465 hom., cov: 33)
  • Exomes 𝑓: 0.20 (34038 hom.)
• Consequence: NLRP1 NM_033004.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.04
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-5583844-C-G is Benign according to our data. Variant chr17-5583844-C-G is described in ClinVar as Benign. ClinVar VariationId is 403241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

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.114G>C	p.Ser38Ser	synonymous	Exon 1 of 17	NP_127497.1	Q9C000-1
	NLRP1	NM_033006.4		c.114G>C	p.Ser38Ser	synonymous	Exon 1 of 16	NP_127499.1	Q9C000-4
	NLRP1	NM_014922.5		c.114G>C	p.Ser38Ser	synonymous	Exon 1 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.114G>C	p.Ser38Ser	synonymous	Exon 1 of 17	ENSP00000460475.1	Q9C000-1
	NLRP1	ENST00000354411.8	TSL:1	c.114G>C	p.Ser38Ser	synonymous	Exon 1 of 16	ENSP00000346390.3	Q9C000-4
	NLRP1	ENST00000269280.9	TSL:1	c.114G>C	p.Ser38Ser	synonymous	Exon 2 of 17	ENSP00000269280.4	Q9C000-2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25905 AN: 152078 Hom.: 3472 Cov.: 33

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.247 AC: 45290 AN: 183436 AF XY: 0.254

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.671

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.198 AC: 280278 AN: 1417280 Hom.: 34038 Cov.: 34 AF XY: 0.203 AC XY: 142319 AN XY: 701002

African (AFR) AF: 0.0353 AC: 1154 AN: 32664

American (AMR) AF: 0.225 AC: 8635 AN: 38448

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 5880 AN: 25414

East Asian (EAS) AF: 0.620 AC: 23231 AN: 37450

South Asian (SAS) AF: 0.376 AC: 30468 AN: 81076

European-Finnish (FIN) AF: 0.240 AC: 12100 AN: 50356

Middle Eastern (MID) AF: 0.208 AC: 1183 AN: 5694

European-Non Finnish (NFE) AF: 0.170 AC: 185035 AN: 1087534

Other (OTH) AF: 0.215 AC: 12592 AN: 58644

GnomAD4 genome AF: 0.170 AC: 25889 AN: 152198 Hom.: 3465 Cov.: 33 AF XY: 0.181 AC XY: 13482 AN XY: 74394

African (AFR) AF: 0.0426 AC: 1772 AN: 41560

American (AMR) AF: 0.195 AC: 2983 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3470

East Asian (EAS) AF: 0.671 AC: 3459 AN: 5156

South Asian (SAS) AF: 0.386 AC: 1860 AN: 4816

European-Finnish (FIN) AF: 0.251 AC: 2654 AN: 10594

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11699 AN: 67982

Other (OTH) AF: 0.190 AC: 401 AN: 2112

Alfa AF: 0.146 Hom.: 627

Bravo AF: 0.161

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autoinflammation with arthritis and dyskeratosis (1)
-	-	1	Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (1)
-	-	1	NLRP1-related disorder (1)
-	-	1	Respiratory papillomatosis, juvenile recurrent, congenital (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.65
DANN	Benign	0.47
PhyloP100		-5.0
PromoterAI		0.20	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs884367; hg19: chr17-5487164; COSMIC: COSV52567290; COSMIC: COSV52567290;