chr2-32250855-T-A

Position:

• chr2-32250855-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001199138.2(NLRC4):​c.1009A>T​(p.Thr337Ser) variant causes a missense change. 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, single submitter P:2
• Conservation: PhyloP100: 4.24

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 2-32250855-T-A is Pathogenic according to our data. Variant chr2-32250855-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 156462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRC4	NM_001199138.2	c.1009A>T	p.Thr337Ser	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.1009A>T	p.Thr337Ser	missense_variant	4/9	1	NM_001199138.2	ENSP00000385428	P1
	ENST00000697331.1	n.2994-2480T>A		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

Periodic fever-infantile enterocolitis-autoinflammatory syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

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

May 24, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect NLRC4 protein function (PMID: 25217959, 29326099). This variant has been observed in individual(s) with autoinflammation with recurrent macrophage activation syndrome (PMID: 25217959). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 156462). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 337 of the NLRC4 protein (p.Thr337Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.63	.;.;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.010	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.83
MutPred		0.77		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.69
MPC		0.72
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.31
gMVP		0.73

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: rs587777840; hg19: chr2-32475924;