rs199475953

Variant names:

• chr2-32250936-G-A
• rs199475953
• NM_001199138.2:c.928C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-32250936-G-A
• chr2-32250936-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_001199138.2(NLRC4):​c.928C>T​(p.Arg310*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NLRC4 NM_001199138.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 0.452

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152238) while in subpopulation NFE AF= 0.000279 (19/68012). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRC4	NM_001199138.2	c.928C>T	p.Arg310*	stop_gained	Exon 4 of 9	ENST00000402280.6	NP_001186067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6	c.928C>T	p.Arg310*	stop_gained	Exon 4 of 9	1	NM_001199138.2	ENSP00000385428.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251260 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000150 AC: 219 AN: 1461760 Hom.: 0 Cov.: 40 AF XY: 0.000161 AC XY: 117 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74444

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1 Other:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NLRC4: BS1 -

Aug 11, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NLRC4 p.R310* variant was identified in 1 of 392 proband chromosomes (frequency: 0.00255) from individuals with systemic autoinflammatory diseases (Karacan_2019_PMID:30783801). The variant was also reported in another case study in a female child with an auto-inflammatory syndrome phenotype (Sleptsova_2016). The variant was identified in dbSNP (ID: rs199475953) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 48 of 282654 chromosomes at a frequency of 0.0001698 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 40 of 129004 chromosomes (freq: 0.00031), Latino in 5 of 35434 chromosomes (freq: 0.000141), Other in 1 of 7224 chromosomes (freq: 0.000138) and European (Finnish) in 2 of 25110 chromosomes (freq: 0.00008), but was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. The c.928C>T variant leads to a premature stop codon at position 310 which is predicted to lead to a truncated or absent protein and loss of function. The role of NLRC4 loss of function variants in disease is currently not well established. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

-

Human Evolutionary Genetics, Institut Pasteur

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Uncertain:1

Aug 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NLRC4 c.928C>T (p.Arg310X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however the molecular mechanism of disease attributed to NLRC4 is gain-of-function. The variant allele was found at a frequency of 0.00017 in 251260 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NLRC4 causing NLRC4-Related Disorders, allowing no conclusion about variant significance. c.928C>T has been reported in the literature in heterozygous individuals affected with clinical features of NLRC4-Related Disorders (e.g., Popplewell_2020, Karacan_2019), however, these report(s) do not provide unequivocal conclusions about association of the variant with NLRC4-Related Disorders. c.928C>T has also been identified in unaffected relatives of affected individuals with the variant (Popplewell_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30783801, 32529290). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified it as a variant of uncertain significance, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Periodic fever-infantile enterocolitis-autoinflammatory syndrome Uncertain:1

Nov 14, 2024

Department of Human Genetics, Hannover Medical School

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: none -

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

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg310*) in the NLRC4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NLRC4 cause disease. This variant is present in population databases (rs199475953, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with systemic autoinflammatory disease (PMID: 30783801). ClinVar contains an entry for this variant (Variation ID: 103085). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.074	N
Vest4		0.93
GERP RS		2.4

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: rs199475953; hg19: chr2-32476005; COSMIC: COSV100707327;