chr19-55896115-C-G

Position:

• chr19-55896115-C-G

Variant summary

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

The NM_176810.2(NLRP13):​c.2962G>C​(p.Ala988Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.857

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 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=0.2619177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.2962G>C	p.Ala988Pro	missense_variant	11/11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.2962G>C	p.Ala988Pro	missense_variant	11/12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.2962G>C	p.Ala988Pro	missense_variant	11/11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.2962G>C	p.Ala988Pro	missense_variant	11/12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Nov 09, 2024

The c.2962G>C (p.A988P) alteration is located in exon 11 (coding exon 11) of the NLRP13 gene. This alteration results from a G to C substitution at nucleotide position 2962, causing the alanine (A) at amino acid position 988 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	0.61
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0052	.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.73	.;N
REVEL	Benign	0.10
Sift	Benign	0.29	.;T
Sift4G	Benign	0.31	T;T
Polyphen		0.73	.;P
Vest4		0.35
MutPred		0.63		Loss of catalytic residue at A988 (P = 0.0262);Loss of catalytic residue at A988 (P = 0.0262);
MVP		0.46
MPC		0.047
ClinPred		0.22	T
GERP RS		0.38
Varity_R		0.15
gMVP		0.36

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: chr19-56407481;