rs61754192

Positions:

chr2-32224763-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001199138.2(NLRC4):c.2785G>T(p.Ala929Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,550,250 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 4 hom., cov: 32)

Exomes 𝑓: 0.011 ( 99 hom. )

Consequence

NLRC4
NM_001199138.2 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.453

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049054623).

BP6

Variant 2-32224763-C-A is Benign according to our data. Variant chr2-32224763-C-A is described in ClinVar as [Benign]. Clinvar id is 475254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32224763-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00769 (1162/151194) while in subpopulation NFE AF= 0.0115 (779/67892). AF 95% confidence interval is 0.0108. There are 4 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1162 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NLRC4	NM_001199138.2 linkuse as main transcript	c.2785G>T	p.Ala929Ser	missense_variant, splice_region_variant	9/9	ENST00000402280.6	NP_001186067.1
NLRC4	NM_001199139.1 linkuse as main transcript	c.2785G>T	p.Ala929Ser	missense_variant, splice_region_variant	9/9		NP_001186068.1
NLRC4	NM_021209.4 linkuse as main transcript	c.2785G>T	p.Ala929Ser	missense_variant, splice_region_variant	9/9		NP_067032.3
NLRC4	NM_001302504.1 linkuse as main transcript	c.790G>T	p.Ala264Ser	missense_variant, splice_region_variant	8/8		NP_001289433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 linkuse as main transcript	c.2785G>T	p.Ala929Ser	missense_variant, splice_region_variant	9/9	1	NM_001199138.2	ENSP00000385428	P1	Q9NPP4-1

Frequencies

GnomAD3 genomes

AF:

0.00769

AC:

1162

AN:

151078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00964

Gnomad ASJ

AF:

0.00867

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000836

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00771

GnomAD3 exomes

AF:

0.00754

AC:

1589

AN:

210810

Hom.:

AF XY:

0.00794

AC XY:

913

AN XY:

114948

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00429

Gnomad ASJ exome

AF:

0.00528

Gnomad EAS exome

AF:

0.0000611

Gnomad SAS exome

AF:

0.00143

Gnomad FIN exome

AF:

0.0100

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0109

AC:

15244

AN:

1399056

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

7326

AN XY:

693254

show subpopulations

Gnomad4 AFR exome

AF:

0.00145

Gnomad4 AMR exome

AF:

0.00501

Gnomad4 ASJ exome

AF:

0.00627

Gnomad4 EAS exome

AF:

0.0000518

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.00877

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.00985

GnomAD4 genome

AF:

0.00769

AC:

1162

AN:

151194

Hom.:

Cov.:

AF XY:

0.00762

AC XY:

562

AN XY:

73796

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00963

Gnomad4 ASJ

AF:

0.00867

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000837

Gnomad4 FIN

AF:

0.0104

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00763

Alfa

AF:

0.00993

Hom.:

Bravo

AF:

0.00750

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0127

AC:

109

ExAC

AF:

0.00676

AC:

820

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NLRC4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 10, 2021

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 11, 2022

- -

NLRC4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.8

DANN

Benign

0.64

DEOGEN2

Benign

0.096

T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.50

.;.;T;T

MetaRNN

Benign

0.0049

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;.;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.030

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.50

T;T;T;T

Polyphen

0.0020

B;B;B;B

Vest4

0.20

MVP

0.31

MPC

0.19

ClinPred

0.00065

GERP RS

-2.1

Varity_R

0.038

gMVP

0.078

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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