2-32224597-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001199138.2(NLRC4):c.2951T>C(p.Val984Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRC4	NM_001199138.2	c.2951T>C	p.Val984Ala	missense_variant	9/9	ENST00000402280.6
NLRC4	NM_001199139.1	c.2951T>C	p.Val984Ala	missense_variant	9/9
NLRC4	NM_021209.4	c.2951T>C	p.Val984Ala	missense_variant	9/9
NLRC4	NM_001302504.1	c.956T>C	p.Val319Ala	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRC4	ENST00000402280.6	c.2951T>C	p.Val984Ala	missense_variant	9/9	1	NM_001199138.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461650 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 26, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NLRC4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 984 of the NLRC4 protein (p.Val984Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M;M;.;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;D;D
Polyphen		0.38	B;B;P;B
Vest4		0.68
MutPred		0.59		Loss of stability (P = 0.019);Loss of stability (P = 0.019);.;Loss of stability (P = 0.019);
MVP		0.69
MPC		0.75
ClinPred		0.96	D
GERP RS		3.4
Varity_R		0.20
gMVP		0.44

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: rs1573460915; hg19: chr2-32449666;