rs587781260

Variant names:

• chr2-32250842-A-G
• rs587781260
• NM_001199138.2:c.1022T>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 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 (★★). ClinVar reports functional evidence for this variant: "SCV002235148: Experimental studies have shown that this variant affects NLRC4 protein function (PMID:25217960, 29778503).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V341L) has been classified 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
• Publications: 42 publications found

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: Illumina, Orphanet, Labcorp Genetics (formerly Invitae)
• familial cold autoinflammatory syndrome 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289727 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002235148: Experimental studies have shown that this variant affects NLRC4 protein function (PMID: 25217960, 29778503).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001199138.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-32250843-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 989330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 143224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199138.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	NM_001199138.2	MANE Select	c.1022T>C	p.Val341Ala	missense	Exon 4 of 9	NP_001186067.1	Q9NPP4-1
	NLRC4	NM_001199139.1		c.1022T>C	p.Val341Ala	missense	Exon 4 of 9	NP_001186068.1	Q9NPP4-1
	NLRC4	NM_021209.4		c.1022T>C	p.Val341Ala	missense	Exon 4 of 9	NP_067032.3	Q9NPP4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.1022T>C	p.Val341Ala	missense	Exon 4 of 9	ENSP00000385428.1	Q9NPP4-1
	NLRC4	ENST00000360906.9	TSL:1	c.1022T>C	p.Val341Ala	missense	Exon 4 of 9	ENSP00000354159.5	Q9NPP4-1
	NLRC4	ENST00000342905.10	TSL:1	c.262+1577T>C		intron	N/A	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Periodic fever-infantile enterocolitis-autoinflammatory syndrome (1)
1	-	-	Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 (1)
1	-	-	Syndrome of entercolitis and autoinflmmation caused by mutation of NLRC4 (SCAN4) (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.85		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

Other links and lift over

dbSNP: rs587781260; hg19: chr2-32475911;