19-55954768-G-A

Position:

• chr19-55954768-G-A

Variant summary

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

The NM_176811.2(NLRP8):​c.710G>A​(p.Arg237His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: NLRP8 NM_176811.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520

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 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=0.030857265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP8	NM_176811.2	c.710G>A	p.Arg237His	missense_variant	3/10	ENST00000291971.7
NLRP8	NM_001317000.1	c.710G>A	p.Arg237His	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP8	ENST00000291971.7	c.710G>A	p.Arg237His	missense_variant	3/10	1	NM_176811.2	P2
NLRP8	ENST00000590542.1	c.710G>A	p.Arg237His	missense_variant	3/10	1		A2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251330 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000499 AC: 729 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000469 AC XY: 341 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000616

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74356

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000600

EpiControl AF: 0.000356

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

Jun 07, 2023

The c.710G>A (p.R237H) alteration is located in exon 3 (coding exon 3) of the NLRP8 gene. This alteration results from a G to A substitution at nucleotide position 710, causing the arginine (R) at amino acid position 237 to be replaced by a histidine (H). 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	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.2
DANN	Benign	0.90
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.6	N;.
REVEL	Benign	0.22
Sift	Benign	0.56	T;.
Sift4G	Benign	0.56	T;T
Polyphen		0.20	B;P
Vest4		0.13
MVP		0.11
MPC		0.18
ClinPred		0.059	T
GERP RS		-4.1
Varity_R		0.018
gMVP		0.35

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: rs142225833; hg19: chr19-56466134; COSMIC: COSV52596681;