rs199475953

Positions:

chr2-32250936-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001199138.2(NLRC4):c.928C>T(p.Arg310Ter) 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: 0.452

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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/exons	MANE	Protein	UniProt
NLRC4	NM_001199138.2 linkuse as main transcript	c.928C>T	p.Arg310Ter	stop_gained	4/9	ENST00000402280.6	NP_001186067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 linkuse as main transcript	c.928C>T	p.Arg310Ter	stop_gained	4/9	1	NM_001199138.2	ENSP00000385428	P1	Q9NPP4-1
	ENST00000697331.1 linkuse as main transcript	n.2994-2399G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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:

AN:

251260

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135784

show subpopulations

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.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727194

show subpopulations

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:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74444

show subpopulations

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.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 11, 2019	- -
not provided, no classification provided	literature only	Human Evolutionary Genetics, Institut Pasteur	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NLRC4: BS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 22, 2023

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;C4015276:Familial cold autoinflammatory syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

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

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.074

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over