16-57023797-C-T

Position:

• chr16-57023797-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384950.1(NLRC5):​c.368C>T​(p.Pro123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NLRC5 NM_001384950.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

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]

NLRC5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23680305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRC5	NM_001384950.1	c.368C>T	p.Pro123Leu	missense_variant	5/49	ENST00000688547.1	NP_001371879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC5	ENST00000688547.1	c.368C>T	p.Pro123Leu	missense_variant	5/49		NM_001384950.1	ENSP00000509992.1
NLRC5	ENST00000262510.10	c.368C>T	p.Pro123Leu	missense_variant	5/49	5		ENSP00000262510.6
NLRC5	ENST00000539144.5	c.368C>T	p.Pro123Leu	missense_variant	3/46	5		ENSP00000441727.1
NLRC5	ENST00000539881.5	n.368C>T		non_coding_transcript_exon_variant	5/25	2		ENSP00000441679.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2024

The c.368C>T (p.P123L) alteration is located in exon 1 (coding exon 1) of the NLRC5 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the proline (P) at amino acid position 123 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T;.
Eigen	Benign	0.069
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.21
Sift	Benign	0.036	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.88	P;P;.
Vest4		0.39
MutPred		0.22		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.55
MPC		0.77
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.28

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: rs2060947445; hg19: chr16-57057709;