16-57025539-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384950.1(NLRC5):ā€‹c.596T>Cā€‹(p.Val199Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,574 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

NLRC5
NM_001384950.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.18
Variant links:
Genes affected
NLRC5 (HGNC:29933): (NLR family CARD domain containing 5) This gene encodes a member of the caspase recruitment domain-containing NLR family. This gene plays a role in cytokine response and antiviral immunity through its inhibition of NF-kappa-B activation and negative regulation of type I interferon signaling pathways. [provided by RefSeq, Oct 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.017374903).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NLRC5NM_001384950.1 linkuse as main transcriptc.596T>C p.Val199Ala missense_variant 6/49 ENST00000688547.1 NP_001371879.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NLRC5ENST00000688547.1 linkuse as main transcriptc.596T>C p.Val199Ala missense_variant 6/49 NM_001384950.1 ENSP00000509992 P2Q86WI3-1
NLRC5ENST00000262510.10 linkuse as main transcriptc.596T>C p.Val199Ala missense_variant 6/495 ENSP00000262510 P2Q86WI3-1
NLRC5ENST00000539144.5 linkuse as main transcriptc.596T>C p.Val199Ala missense_variant 4/465 ENSP00000441727 A2Q86WI3-4
NLRC5ENST00000539881.5 linkuse as main transcriptc.596T>C p.Val199Ala missense_variant, NMD_transcript_variant 6/252 ENSP00000441679 Q86WI3-3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152066
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000399
AC:
10
AN:
250718
Hom.:
0
AF XY:
0.0000517
AC XY:
7
AN XY:
135426
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461390
Hom.:
0
Cov.:
34
AF XY:
0.0000124
AC XY:
9
AN XY:
726910
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74404
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000659
AC:
8
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 01, 2021The c.596T>C (p.V199A) alteration is located in exon 1 (coding exon 1) of the NLRC5 gene. This alteration results from a T to C substitution at nucleotide position 596, causing the valine (V) at amino acid position 199 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
1.3
DANN
Benign
0.24
DEOGEN2
Benign
0.0034
T;T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.32
.;T;T
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.017
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
0.14
N;N;N
REVEL
Benign
0.048
Sift
Benign
0.88
T;T;T
Sift4G
Benign
0.50
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.032
MutPred
0.38
Gain of disorder (P = 0.039);Gain of disorder (P = 0.039);Gain of disorder (P = 0.039);
MVP
0.11
MPC
0.29
ClinPred
0.85
D
GERP RS
-1.7
Varity_R
0.025
gMVP
0.26

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.

Other links and lift over

dbSNP: rs539891659; hg19: chr16-57059451; API