19-55898872-T-C

Position:

• chr19-55898872-T-C

Variant summary

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

The NM_176810.2(NLRP13):​c.2855A>G​(p.His952Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.79

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03487858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.2855A>G	p.His952Arg	missense_variant	10/11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.2855A>G	p.His952Arg	missense_variant	10/12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.2855A>G	p.His952Arg	missense_variant	10/11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.2855A>G	p.His952Arg	missense_variant	10/12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Jul 27, 2024

The c.2855A>G (p.H952R) alteration is located in exon 10 (coding exon 10) of the NLRP13 gene. This alteration results from a A to G substitution at nucleotide position 2855, causing the histidine (H) at amino acid position 952 to be replaced by an arginine (R). 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	0.058
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.039
DANN	Benign	0.11
DEOGEN2	Benign	0.00029	.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.36	.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.16	.;N
REVEL	Benign	0.0080
Sift	Benign	0.79	.;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0	.;B
Vest4		0.092
MutPred		0.25		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.18
MPC		0.017
ClinPred		0.021	T
GERP RS		-5.6
Varity_R		0.029
gMVP		0.16

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: rs1163997948; hg19: chr19-56410238;