Genetic Variant NM_001391958.1:c.1288G>A (chr11-7960324-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001391958.1(NLRP10):c.1288G>A(p.Glu430Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NLRP10
NM_001391958.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99

Variant links:

Genes affected

NLRP10 (HGNC:21464): (NLR family pyrin domain containing 10) Members of the NALP protein family typically contain a NACHT domain, a NACHT-associated domain (NAD), a C-terminal leucine-rich repeat (LRR) region, and an N-terminal pyrin domain (PYD). The protein encoded by this gene belongs to the NALP protein family despite lacking the LRR region. This protein likely plays a regulatory role in the innate immune system. The protein belongs to the signal-induced multiprotein complex, the inflammasome, that activates the pro-inflammatory caspases, caspase-1 and caspase-5. Other experiments indicate that this gene acts as a multifunctional negative regulator of inflammation and apoptosis. [provided by RefSeq, Jul 2008]

NLRP10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP10	NM_001391958.1 link	c.1288G>A	p.Glu430Lys	missense_variant	Exon 3 of 3	ENST00000691676.1	NP_001378887.1
NLRP10	NM_176821.4 link	c.1288G>A	p.Glu430Lys	missense_variant	Exon 2 of 2		NP_789791.1	Q86W26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP10	ENST00000691676.1 link	c.1288G>A	p.Glu430Lys	missense_variant	Exon 3 of 3		NM_001391958.1	ENSP00000509542.1		Q86W26
NLRP10	ENST00000328600.3 link	c.1288G>A	p.Glu430Lys	missense_variant	Exon 2 of 2	1		ENSP00000327763.2		Q86W26

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000668

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1288G>A (p.E430K) alteration is located in exon 2 (coding exon 2) of the NLRP10 gene. This alteration results from a G to A substitution at nucleotide position 1288, causing the glutamic acid (E) at amino acid position 430 to be replaced by a lysine (K). 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

0.18

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.076

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.56

M_CAP

Uncertain

0.088

MetaRNN

Uncertain

0.67

MetaSVM

Uncertain

-0.087

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.034

Polyphen

1.0

Vest4

0.61

MutPred

0.41

Gain of ubiquitination at E430 (P = 0.0198);

MVP

0.78

MPC

0.45

ClinPred

0.95

GERP RS

3.7

Varity_R

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over