19-55898809-C-T

Position:

• chr19-55898809-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_176810.2(NLRP13):​c.2918G>A​(p.Cys973Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

NLRP13 (HGNC:22937): (NLR family pyrin domain containing 13) This gene encodes a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family. It has an N-terminal pyrin domain, followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NLRP proteins are implicated in the activation of proinflammatory caspases through multiprotein complexes called inflammasomes. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.2918G>A	p.Cys973Tyr	missense_variant	10/11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.2918G>A	p.Cys973Tyr	missense_variant	10/12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.2918G>A	p.Cys973Tyr	missense_variant	10/11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.2918G>A	p.Cys973Tyr	missense_variant	10/12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Jun 17, 2024

The c.2918G>A (p.C973Y) alteration is located in exon 10 (coding exon 10) of the NLRP13 gene. This alteration results from a G to A substitution at nucleotide position 2918, causing the cysteine (C) at amino acid position 973 to be replaced by a tyrosine (Y). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.068	.;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.0060
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0066	T
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.2	.;M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-9.8	.;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.92	.;P
Vest4		0.51
MutPred		0.80		Gain of ubiquitination at K970 (P = 0.0751);Gain of ubiquitination at K970 (P = 0.0751);
MVP		0.66
MPC		0.11
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.73
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-56410175;