16-57025587-C-G

Position:

• chr16-57025587-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384950.1(NLRC5):​c.644C>G​(p.Thr215Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NLRC5 NM_001384950.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.453

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]

ACMG classification

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=0.048479617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRC5	NM_001384950.1	c.644C>G	p.Thr215Ser	missense_variant	6/49	ENST00000688547.1	NP_001371879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC5	ENST00000688547.1	c.644C>G	p.Thr215Ser	missense_variant	6/49		NM_001384950.1	ENSP00000509992	P2
NLRC5	ENST00000262510.10	c.644C>G	p.Thr215Ser	missense_variant	6/49	5		ENSP00000262510	P2
NLRC5	ENST00000539144.5	c.644C>G	p.Thr215Ser	missense_variant	4/46	5		ENSP00000441727	A2
NLRC5	ENST00000539881.5	c.644C>G	p.Thr215Ser	missense_variant, NMD_transcript_variant	6/25	2		ENSP00000441679

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Mar 25, 2024

The c.644C>G (p.T215S) alteration is located in exon 1 (coding exon 1) of the NLRC5 gene. This alteration results from a C to G substitution at nucleotide position 644, causing the threonine (T) at amino acid position 215 to be replaced by a serine (S). 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	0.098
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.0
DANN	Benign	0.27
DEOGEN2	Benign	0.0020	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.48	.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.024	B;B;B
Vest4		0.051
MutPred		0.33		Gain of disorder (P = 0.0806);Gain of disorder (P = 0.0806);Gain of disorder (P = 0.0806);
MVP		0.23
MPC		0.22
ClinPred		0.023	T
GERP RS		1.7
Varity_R		0.033
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-57059499;