chr17-5514787-G-A

Variant names:

• chr17-5514787-G-A
• rs74929853
• NM_033004.4:c.4389C>T

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.4389C>T​(p.Gly1463Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,844 control chromosomes in the GnomAD database, including 1,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (127 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1602 hom.)
• Consequence: NLRP1 NM_033004.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.00
• Publications: 5 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-5514787-G-A is Benign according to our data. Variant chr17-5514787-G-A is described in ClinVar as [Benign]. Clinvar id is 1165834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.4389C>T	p.Gly1463Gly	synonymous_variant	Exon 17 of 17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.4389C>T	p.Gly1463Gly	synonymous_variant	Exon 17 of 17	1	NM_033004.4	ENSP00000460475.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1644 AN: 152088 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0304 AC: 7590 AN: 249382 AF XY: 0.0365

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000548

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0140 AC: 20460 AN: 1461638 Hom.: 1602 Cov.: 32 AF XY: 0.0183 AC XY: 13333 AN XY: 727124

African (AFR) AF: 0.00251 AC: 84 AN: 33458

American (AMR) AF: 0.000784 AC: 35 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.129 AC: 5107 AN: 39696

South Asian (SAS) AF: 0.157 AC: 13513 AN: 86246

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5758

European-Non Finnish (NFE) AF: 0.000387 AC: 430 AN: 1111938

Other (OTH) AF: 0.0203 AC: 1225 AN: 60378

GnomAD4 genome AF: 0.0109 AC: 1666 AN: 152206 Hom.: 127 Cov.: 32 AF XY: 0.0143 AC XY: 1065 AN XY: 74408

African (AFR) AF: 0.00250 AC: 104 AN: 41544

American (AMR) AF: 0.00105 AC: 16 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.128 AC: 662 AN: 5176

South Asian (SAS) AF: 0.167 AC: 806 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67994

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.00155 Hom.: 2

Bravo AF: 0.00754

Asia WGS AF: 0.178 AC: 620 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.77
DANN	Benign	0.36
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs74929853; hg19: chr17-5418107;