11-7038647-G-A

Position:

• chr11-7038647-G-A

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.61G>A​(p.Glu21Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000828 in 1,613,846 control chromosomes in the GnomAD database, including 18 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 Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0013 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (13 hom.)
• Consequence: NLRP14 NM_176822.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.493

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=0.009460777).
• BP6: Variant 11-7038647-G-A is Benign according to our data. Variant chr11-7038647-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052777.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00127 (193/152202) while in subpopulation EAS AF= 0.0322 (167/5184). AF 95% confidence interval is 0.0282. There are 5 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP14	NM_176822.4	c.61G>A	p.Glu21Lys	missense_variant	2/12	ENST00000299481.5	NP_789792.1
NLRP14	XM_011520044.2	c.61G>A	p.Glu21Lys	missense_variant	2/11		XP_011518346.1
NLRP14	XM_047426867.1	c.61G>A	p.Glu21Lys	missense_variant	2/11		XP_047282823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP14	ENST00000299481.5	c.61G>A	p.Glu21Lys	missense_variant	2/12	5	NM_176822.4	ENSP00000299481	P1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152084 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.00228 AC: 573 AN: 251348 Hom.: 8 AF XY: 0.00211 AC XY: 287 AN XY: 135856

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0297

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000783 AC: 1144 AN: 1461644 Hom.: 13 Cov.: 32 AF XY: 0.000773 AC XY: 562 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0251

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152202 Hom.: 5 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74404

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0322

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00128 Hom.: 5

Bravo AF: 0.00147

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NLRP14-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as likely 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	0.24
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.48
MVP		0.69
MPC		0.15
ClinPred		0.089	T
GERP RS		2.3
Varity_R		0.56
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11041150; hg19: chr11-7059878;