19-55948044-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_176811.2(NLRP8):c.142G>A(p.Val48Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,614,080 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (69 hom.)
• Consequence: NLRP8 NM_176811.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.205

Genes affected

NLRP8 (HGNC:22940): (NLR family pyrin domain containing 8) This gene encodes a member of the nucleotide-binding oligomerization domain/ leucine rich repeat/ pyrin domain containing (NLRP) subfamily, which belongs to the Nod-like receptor family of proteins. NLRP genes play roles in the mammalian innate immune system through inflammasome formation and activation of caspases. In addition, NLRP genes have been found to function during mammalian reproduction. Consistent with a function during human preimplantation development, this gene is expressed at high levels in oocytes with decreased levels in embryos. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060155094).
• BP6: Variant 19-55948044-G-A is Benign according to our data. Variant chr19-55948044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 931744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP8	NM_176811.2	c.142G>A	p.Val48Met	missense_variant	1/10	ENST00000291971.7
NLRP8	NM_001317000.1	c.142G>A	p.Val48Met	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP8	ENST00000291971.7	c.142G>A	p.Val48Met	missense_variant	1/10	1	NM_176811.2	P2
NLRP8	ENST00000590542.1	c.142G>A	p.Val48Met	missense_variant	1/10	1		A2

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1144 AN: 152102 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00673 AC: 1690 AN: 251292 Hom.: 14 AF XY: 0.00687 AC XY: 933 AN XY: 135846

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.00709

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00767 AC: 11215 AN: 1461860 Hom.: 69 Cov.: 61 AF XY: 0.00745 AC XY: 5420 AN XY: 727230

Gnomad4 AFR exome AF: 0.00771

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.00796

Gnomad4 OTH exome AF: 0.00647

GnomAD4 genome AF: 0.00755 AC: 1150 AN: 152220 Hom.: 3 Cov.: 32 AF XY: 0.00786 AC XY: 585 AN XY: 74416

Gnomad4 AFR AF: 0.00689

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00639 Hom.: 6

Bravo AF: 0.00608

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00682 AC: 828

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 26, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	NLRP8: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.0012	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.47	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.027	D;.
Sift4G	Uncertain	0.047	D;D
Polyphen		0.96	D;D
Vest4		0.14
MVP		0.14
MPC		0.29
ClinPred		0.034	T
GERP RS		-4.5
Varity_R		0.037
gMVP		0.059

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: rs61738689; hg19: chr19-56459410;