11-7039717-C-T

Position:

• chr11-7039717-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_176822.4(NLRP14):​c.293C>T​(p.Ser98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 1,611,794 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (66 hom., cov: 31)
  • Exomes 𝑓: 0.032 (848 hom.)
• Consequence: NLRP14 NM_176822.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.924

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028524697).
• BP6: Variant 11-7039717-C-T is Benign according to our data. Variant chr11-7039717-C-T is described in ClinVar as [Benign]. Clinvar id is 3059218.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3522/152224) while in subpopulation NFE AF= 0.0358 (2437/68014). AF 95% confidence interval is 0.0346. There are 66 homozygotes in gnomad4. There are 1666 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP14	NM_176822.4	c.293C>T	p.Ser98Leu	missense_variant	3/12	ENST00000299481.5	NP_789792.1
NLRP14	XM_011520044.2	c.293C>T	p.Ser98Leu	missense_variant	3/11		XP_011518346.1
NLRP14	XM_047426867.1	c.293C>T	p.Ser98Leu	missense_variant	3/11		XP_047282823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP14	ENST00000299481.5	c.293C>T	p.Ser98Leu	missense_variant	3/12	5	NM_176822.4	ENSP00000299481.5

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3523 AN: 152106 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0272

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0358

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0271 AC: 6809 AN: 251280 Hom.: 118 AF XY: 0.0282 AC XY: 3831 AN XY: 135808

Gnomad AFR exome AF: 0.00584

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0343

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0305

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0369

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0321 AC: 46850 AN: 1459570 Hom.: 848 Cov.: 30 AF XY: 0.0322 AC XY: 23396 AN XY: 726228

Gnomad4 AFR exome AF: 0.00604

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0355

Gnomad4 OTH exome AF: 0.0288

GnomAD4 genome AF: 0.0231 AC: 3522 AN: 152224 Hom.: 66 Cov.: 31 AF XY: 0.0224 AC XY: 1666 AN XY: 74422

Gnomad4 AFR AF: 0.00645

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0358

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0334 Hom.: 158

Bravo AF: 0.0219

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0405 AC: 156

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0357 AC: 307

ExAC AF: 0.0286 AC: 3477

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0335

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NLRP14-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.61
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.026
Sift	Benign	0.062	T
Sift4G	Uncertain	0.010	D
Polyphen		0.081	B
Vest4		0.098
MPC		0.018
ClinPred		0.00038	T
GERP RS		1.5
Varity_R		0.083
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs117823353; hg19: chr11-7060948;