rs17280682

Positions:

• chr11-7070338-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176822.4(NLRP14):​c.3028C>T​(p.Leu1010Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,608,730 control chromosomes in the GnomAD database, including 31,805 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2148 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29657 hom.)
• Consequence: NLRP14 NM_176822.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.99

Genes affected

NLRP14 (HGNC:22939): (NLR family pyrin domain containing 14) The protein encoded by this gene belongs to the NALP protein family. Members of the NALP protein family typically contain a NACHT domain, a NACHT-associated domain (NAD), a C-terminal leucine-rich repeat (LRR) region, and an N-terminal pyrin domain (PYD). This protein may play a regulatory role in the innate immune system as similar family members belong to the signal-induced multiprotein complex, the inflammasome, that activates the pro-inflammatory caspases, caspase-1 and caspase-5. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010507703).
• BP6: Variant 11-7070338-C-T is Benign according to our data. Variant chr11-7070338-C-T is described in ClinVar as [Benign]. Clinvar id is 1222316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP14	NM_176822.4	c.3028C>T	p.Leu1010Phe	missense_variant	11/12	ENST00000299481.5
NLRP14	XM_011520044.2	c.2857C>T	p.Leu953Phe	missense_variant	10/11
NLRP14	XM_047426867.1	c.2857C>T	p.Leu953Phe	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP14	ENST00000299481.5	c.3028C>T	p.Leu1010Phe	missense_variant	11/12	5	NM_176822.4	P1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23045 AN: 152006 Hom.: 2148 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.0852

Gnomad FIN AF: 0.0972

Gnomad MID AF: 0.186

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.148 AC: 37184 AN: 251174 Hom.: 3336 AF XY: 0.151 AC XY: 20460 AN XY: 135756

Gnomad AFR exome AF: 0.0772

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.0896

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.194 AC: 282213 AN: 1456606 Hom.: 29657 Cov.: 29 AF XY: 0.192 AC XY: 139294 AN XY: 725018

Gnomad4 AFR exome AF: 0.0773

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.0188

Gnomad4 SAS exome AF: 0.0976

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.152 AC: 23049 AN: 152124 Hom.: 2148 Cov.: 32 AF XY: 0.145 AC XY: 10795 AN XY: 74376

Gnomad4 AFR AF: 0.0810

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.0147

Gnomad4 SAS AF: 0.0856

Gnomad4 FIN AF: 0.0972

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.182

Alfa AF: 0.201 Hom.: 8023

Bravo AF: 0.154

TwinsUK AF: 0.218 AC: 809

ALSPAC AF: 0.217 AC: 836

ESP6500AA AF: 0.0836 AC: 368

ESP6500EA AF: 0.215 AC: 1848

ExAC AF: 0.149 AC: 18144

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.226

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NLRP14-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.041
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.16
Sift	Benign	0.058	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.71	P
Vest4		0.064
MPC		0.046
ClinPred		0.041	T
GERP RS		4.1
Varity_R		0.18
gMVP		0.20

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: rs17280682; hg19: chr11-7091569;