rs149451729

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001199138.2(NLRC4):c.2357G>T(p.Gly786Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,608,440 control chromosomes in the GnomAD database, including 20 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 16 hom. )

Consequence

NLRC4
NM_001199138.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

NLRC4 (HGNC:16412): (NLR family CARD domain containing 4) This gene encodes a member of the caspase recruitment domain-containing NLR family. Family members play essential roles in innate immune response to a wide range of pathogenic organisms, tissue damage and other cellular stresses. Mutations in this gene result in autoinflammation with infantile enterocolitis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

NLRC4 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021336168).

BP6

Variant 2-32238296-C-A is Benign according to our data. Variant chr2-32238296-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475252.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=3}. Variant chr2-32238296-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (366/152212) while in subpopulation NFE AF= 0.00423 (288/68032). AF 95% confidence interval is 0.00383. There are 4 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NLRC4	NM_001199138.2 linkuse as main transcript	c.2357G>T	p.Gly786Val	missense_variant	6/9	ENST00000402280.6	NP_001186067.1
NLRC4	NM_001199139.1 linkuse as main transcript	c.2357G>T	p.Gly786Val	missense_variant	6/9		NP_001186068.1
NLRC4	NM_021209.4 linkuse as main transcript	c.2357G>T	p.Gly786Val	missense_variant	6/9		NP_067032.3
NLRC4	NM_001302504.1 linkuse as main transcript	c.362G>T	p.Gly121Val	missense_variant	5/8		NP_001289433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 linkuse as main transcript	c.2357G>T	p.Gly786Val	missense_variant	6/9	1	NM_001199138.2	ENSP00000385428	P1	Q9NPP4-1
	ENST00000697331.1 linkuse as main transcript	n.2993+1918C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

366

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00423

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00232

AC:

570

AN:

245338

Hom.:

AF XY:

0.00248

AC XY:

330

AN XY:

132830

show subpopulations

Gnomad AFR exome

AF:

0.000818

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000546

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00399

Gnomad OTH exome

AF:

0.00269

GnomAD4 exome

AF:

0.00392

AC:

5713

AN:

1456228

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

2781

AN XY:

724400

show subpopulations

Gnomad4 AFR exome

AF:

0.000604

Gnomad4 AMR exome

AF:

0.00225

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000718

Gnomad4 FIN exome

AF:

0.000657

Gnomad4 NFE exome

AF:

0.00478

Gnomad4 OTH exome

AF:

0.00304

GnomAD4 genome

AF:

0.00240

AC:

366

AN:

152212

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

156

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000891

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00423

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00393

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00239

AC:

290

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Feb 16, 2022	NLRC4 NM_021209.4 exon 6 p.Gly786Val (c.2357G>T): This variant has been reported in the literature in at least 1 individual with Presumed Ocular Histoplasmosis Syndrome (POHS) (Li 2020 32707200). This variant is present in 0.4% (288/68040) of European alleles including 3 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-32238296-C-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:475252). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 08, 2018	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NLRC4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

NLRC4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 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). -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.23

T;T;.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.79

.;.;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.9

L;L;.;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.23

T;T;T;T

Polyphen

0.99

D;D;D;D

Vest4

0.53

MVP

0.52

MPC

0.65

ClinPred

0.023

GERP RS

2.8

Varity_R

0.058

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over