19-55896048-A-G

Variant names:

• chr19-55896048-A-G
• NM_176810.2:c.3029T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_176810.2(NLRP13):​c.3029T>C​(p.Leu1010Pro) variant causes a missense change. 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: 32)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.3029T>C	p.Leu1010Pro	missense_variant	Exon 11 of 11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.3029T>C	p.Leu1010Pro	missense_variant	Exon 11 of 12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.3029T>C	p.Leu1010Pro	missense_variant	Exon 11 of 11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.3029T>C	p.Leu1010Pro	missense_variant	Exon 11 of 12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3029T>C (p.L1010P) alteration is located in exon 11 (coding exon 11) of the NLRP13 gene. This alteration results from a T to C substitution at nucleotide position 3029, causing the leucine (L) at amino acid position 1010 to be replaced by a proline (P). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T
Eigen	Benign	0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.5	.;M
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.4	.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.78
MutPred		0.81		Loss of stability (P = 0.0255);Loss of stability (P = 0.0255);
MVP		0.74
MPC		0.15
ClinPred		0.93	D
GERP RS		2.9
Varity_R		0.38
gMVP		0.51
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr19-56407414; COSMIC: COSV61622134;