dbSNP rs113631419: NLRC4:p.Ala160Thr (chr2-32251386-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001199138.2(NLRC4):c.478G>A(p.Ala160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,062 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A160A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

NLRC4
NM_001199138.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.151

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

periodic fever-infantile enterocolitis-autoinflammatory syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae)
familial cold autoinflammatory syndrome 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

NLRC4 links:

ENSG00000289727 (HGNC:):

ENSG00000289727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013109505).

BP6

Variant 2-32251386-C-T is Benign according to our data. Variant chr2-32251386-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542049.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000736 (112/152238) while in subpopulation NFE AF = 0.00126 (86/68026). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 112 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199138.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRC4	NM_001199138.2	MANE Select	c.478G>A	p.Ala160Thr	missense	Exon 4 of 9	NP_001186067.1	Q9NPP4-1
NLRC4	NM_001199139.1		c.478G>A	p.Ala160Thr	missense	Exon 4 of 9	NP_001186068.1	Q9NPP4-1
NLRC4	NM_021209.4		c.478G>A	p.Ala160Thr	missense	Exon 4 of 9	NP_067032.3	Q9NPP4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.478G>A	p.Ala160Thr	missense	Exon 4 of 9	ENSP00000385428.1	Q9NPP4-1
NLRC4	ENST00000360906.9	TSL:1	c.478G>A	p.Ala160Thr	missense	Exon 4 of 9	ENSP00000354159.5	Q9NPP4-1
NLRC4	ENST00000342905.10	TSL:1	c.262+1033G>A		intron	N/A	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000820

AC:

206

AN:

251196

AF XY:

0.000899

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000971

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00113

AC:

1656

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

853

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.000805

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000880

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00132

AC:

1471

AN:

1111970

Other (OTH)

AF:

0.00116

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

178

268

357

446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152238

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41536

American (AMR)

AF:

0.000588

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000916

Hom.:

Bravo

AF:

0.000744

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000857

AC:

104

EpiCase

AF:

0.00180

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 (2)

Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.50

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.086

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.51

M_CAP

Benign

0.0077

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.3

PhyloP100

-0.15

PrimateAI

Benign

0.38

PROVEAN

Benign

1.2

REVEL

Benign

0.020

Sift

Benign

0.71

Polyphen

0.0

Vest4

0.068

MVP

0.13

MPC

0.20

ClinPred

0.0022

GERP RS

-1.6

Varity_R

0.019

gMVP

0.16

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over