rs587781260

Positions:

• chr2-32250842-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001199138.2(NLRC4):​c.1022T>C​(p.Val341Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.31

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]

ENSG00000289727 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 2-32250842-A-G is Pathogenic according to our data. Variant chr2-32250842-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 143224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRC4	NM_001199138.2	c.1022T>C	p.Val341Ala	missense_variant	4/9	ENST00000402280.6	NP_001186067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6	c.1022T>C	p.Val341Ala	missense_variant	4/9	1	NM_001199138.2	ENSP00000385428.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Periodic fever-infantile enterocolitis-autoinflammatory syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

Syndrome of entercolitis and autoinflmmation caused by mutation of NLRC4 (SCAN4) Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Richard Lifton Laboratory, Yale University School of Medicine

Jul 18, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2015

The V341A variant in the NLRC4 gene has been reported previously in a family with enterocolitis andautoinflammation (Romberg et al., 2014). The variant occurred de novo in the father and was inheritedby two of his sons, presentation of the disease was variable, with death from diffuse alveolar hemorrhageoccurring at 26 days of life in the most severely affected son (Romberg et al., 2014). The V341A substitutionwas not observed in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. TheV341A variant is a conservative amino acid substitution and occurs at a position that is conserved acrossspecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging tothe protein structure/function. A missense de novo variant in a nearby residue (T337S) has been reportedin a patient with autoinflammation with recurrent macrophage activation syndrome (Canna et al., 2014),supporting the functional importance of this region of the protein. Therefore, we interpret this variant as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 341 of the NLRC4 protein (p.Val341Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant has been observed in individual(s) with autoinflammation with infantile enterocolitis (PMID: 25217960, 30864118). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143224). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects NLRC4 protein function (PMID: 25217960, 29778503). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.61	.;.;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.84
MutPred		0.85		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.77
MPC		0.55
ClinPred		0.90	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.82

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: rs587781260; hg19: chr2-32475911;