rs202104062

Variant names:

• chr19-56003724-C-G
• rs202104062
• ENST00000390649.8:c.71C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-56003724-C-G
• chr19-56003724-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000390649.8(NLRP5):​c.71C>G​(p.Thr24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000307 in 1,596,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T24I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: NLRP5 ENST00000390649.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.446
• Publications: 3 publications found

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]

NLRP5 Gene-Disease associations (from GenCC):

• oocyte/zygote/embryo maturation arrest 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000390649.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP5	NM_001433705.1		c.-71-12C>G		intron	N/A	NP_001420634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP5	ENST00000390649.8	TSL:1 MANE Select	c.71C>G	p.Thr24Ser	missense	Exon 2 of 15	ENSP00000375063.3	P59047
	NLRP5	ENST00000850973.1		c.-71-12C>G		intron	N/A	ENSP00000521055.1
	NLRP5	ENST00000597673.1	TSL:5	n.-11C>G		upstream_gene	N/A	ENSP00000471494.1	M0R0W4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235690 AF XY: 0.00000783

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000319 AC: 46 AN: 1444152 Hom.: 0 Cov.: 31 AF XY: 0.0000362 AC XY: 26 AN XY: 717288

African (AFR) AF: 0.00 AC: 0 AN: 32498

American (AMR) AF: 0.00 AC: 0 AN: 40844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 83326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.0000407 AC: 45 AN: 1104644

Other (OTH) AF: 0.0000168 AC: 1 AN: 59520

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000113

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.1
DANN	Benign	0.34
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.45
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.073
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.81	P
Vest4		0.16
MutPred		0.27		Loss of sheet (P = 0.0357)
MVP		0.51
MPC		0.021
ClinPred		0.083	T
GERP RS		0.27
Varity_R		0.055
gMVP		0.050
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202104062; hg19: chr19-56515090;