rs606231460

Positions:

• chr2-32250536-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001199138.2(NLRC4):​c.1328A>C​(p.His443Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H443Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.77

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a region_of_interest Winged-helix domain (WHD) (size 107) in uniprot entity NLRC4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr2-32250535-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 808727.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 2-32250536-T-G is Pathogenic according to our data. Variant chr2-32250536-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 161413.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRC4	NM_001199138.2	c.1328A>C	p.His443Pro	missense_variant	4/9	ENST00000402280.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRC4	ENST00000402280.6	c.1328A>C	p.His443Pro	missense_variant	4/9	1	NM_001199138.2	P1
	ENST00000697331.1	n.2994-2799T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 17, 2014

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2019

This sequence change replaces histidine with proline at codon 443 of the NLRC4 protein (p.His443Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial cold autoinflammatory syndrome in a family (PMID: 25385754). This variant is also known as 1589A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 161413). This variant has been reported to affect NLRC4 protein function (PMID: 25385754, 27974463, 29778503). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Pathogenic	0.90	D;D;D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.54	.;.;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.12	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.69		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);
MVP		0.66
MPC		0.36
ClinPred		0.95	D
GERP RS		3.0
Varity_R		0.83
gMVP		0.65

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: rs606231460; hg19: chr2-32475605;