rs202181446

chr19-56040975-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BS1_Supporting

The NM_153447.4(NLRP5):c.2840T>C(p.Leu947Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000385 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: NLRP5 NM_153447.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.41

Genes affected

NLRP5 (HGNC:21269): (NLR family pyrin domain containing 5) The protein encoded by this gene belongs to the NALP protein family. 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). Expression of this gene is restricted to the oocyte. A mouse gene that encodes a maternal oocyte protein, similar to this encoded protein, is required for normal early embryogenesis. [provided by RefSeq, Jul 2008]

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, 0.873
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000348 (53/152170) while in subpopulation AMR AF= 0.00131 (20/15272). AF 95% confidence interval is 0.000867. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP5	NM_153447.4	c.2840T>C	p.Leu947Pro	missense_variant	11/15	ENST00000390649.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP5	ENST00000390649.8	c.2840T>C	p.Leu947Pro	missense_variant	11/15	1	NM_153447.4	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000261 AC: 65 AN: 249164 Hom.: 0 AF XY: 0.000252 AC XY: 34 AN XY: 135186

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000389 AC: 568 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.000366 AC XY: 266 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000492

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: 0.000478

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74336

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Toriello-Lacassie-Droste syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Apr 17, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.88
MVP		0.76
MPC		0.21
ClinPred		0.23	T
GERP RS		4.4
Varity_R		0.76
gMVP		0.68

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: rs202181446; hg19: chr19-56552341;