17-5514787-G-A

Position:

• chr17-5514787-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033004.4(NLRP1):​c.4389C>T​(p.Gly1463=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.4389C>T	p.Gly1463=	synonymous_variant	17/17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.4389C>T	p.Gly1463=	synonymous_variant	17/17	1	NM_033004.4	ENSP00000460475	P2

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

GnomAD3 exomes AF: 0.0304 AC: 7590 AN: 249382 Hom.: 602 AF XY: 0.0365 AC XY: 4935 AN XY: 135322

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 SAS exome AF: 0.161

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

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.0203

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

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00165 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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.77
DANN	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs74929853; hg19: chr17-5418107;