19-55902174-A-T

Position:

• chr19-55902174-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_176810.2(NLRP13):​c.2650T>A​(p.Cys884Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.907

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.2650T>A	p.Cys884Ser	missense_variant	9/11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.2650T>A	p.Cys884Ser	missense_variant	9/12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.2650T>A	p.Cys884Ser	missense_variant	9/11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.2650T>A	p.Cys884Ser	missense_variant	9/12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74438

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Human Evolutionary Genetics, Institut Pasteur

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.9	.;D
REVEL	Benign	0.12
Sift	Benign	0.43	.;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.34
MutPred		0.79		Gain of disorder (P = 0.0027);Gain of disorder (P = 0.0027);
MVP		0.62
MPC		0.10
ClinPred		0.64	D
GERP RS		1.4
Varity_R		0.18
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs199475877; hg19: chr19-56413540;