19-56003854-G-A

Variant names:

• chr19-56003854-G-A
• rs1981749349
• ENST00000390649.8:c.201G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000390649.8(NLRP5):​c.201G>A​(p.Trp67*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP5 ENST00000390649.8 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	NP_001420634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP5	ENST00000390649.8	TSL:1 MANE Select	c.201G>A	p.Trp67*	stop_gained	Exon 2 of 15	ENSP00000375063.3	P59047
	NLRP5	ENST00000850973.1		c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	ENSP00000521055.1
	NLRP5	ENST00000597673.1	TSL:5	n.120G>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000471494.1	M0R0W4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.25	N
PhyloP100		2.3
Vest4		0.51
GERP RS		3.1
Mutation Taster		=47/153	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1981749349; hg19: chr19-56515220; COSMIC: COSV66764434;