rs937306605

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001199138.2(NLRC4):c.2426A>G(p.Asp809Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NLRC4
NM_001199138.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.603

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

periodic fever-infantile enterocolitis-autoinflammatory syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Labcorp Genetics (formerly Invitae)
familial cold autoinflammatory syndrome 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

NLRC4 links:

ENSG00000289727 (HGNC:):

ENSG00000289727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRC4	NM_001199138.2 link	c.2426A>G	p.Asp809Gly	missense_variant	Exon 6 of 9	ENST00000402280.6	NP_001186067.1	Q9NPP4-1
NLRC4	NM_001199139.1 link	c.2426A>G	p.Asp809Gly	missense_variant	Exon 6 of 9		NP_001186068.1	Q9NPP4-1
NLRC4	NM_021209.4 link	c.2426A>G	p.Asp809Gly	missense_variant	Exon 6 of 9		NP_067032.3	Q9NPP4-1
NLRC4	NM_001302504.1 link	c.431A>G	p.Asp144Gly	missense_variant	Exon 5 of 8		NP_001289433.1	Q9NPP4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 link	c.2426A>G	p.Asp809Gly	missense_variant	Exon 6 of 9	1	NM_001199138.2	ENSP00000385428.1		Q9NPP4-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250996

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111586

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Periodic fever-infantile enterocolitis-autoinflammatory syndrome

Uncertain:1

May 08, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

Uncertain:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 809 of the NLRC4 protein (p.Asp809Gly). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NLRC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 475253). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NLRC4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D;.;D

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.74

.;.;T;T

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.47

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.4

M;M;.;M

PhyloP100

0.60

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.020

D;D;D;D

Polyphen

0.88

P;P;D;P

Vest4

0.50

MutPred

0.36

Loss of stability (P = 0.0658);Loss of stability (P = 0.0658);.;Loss of stability (P = 0.0658);

MVP

0.76

MPC

0.52

ClinPred

0.97

GERP RS

4.6

Varity_R

0.24

gMVP

0.50

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over