rs104895506

Variant names:

• chr19-54938096-G-A
• rs104895506
• NM_001127255.2:c.2077C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-54938096-G-A
• chr19-54938096-G-C
• chr19-54938096-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM5 PP5_Moderate

The NM_001127255.2(NLRP7):​c.2077C>T​(p.Arg693Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000414696: Co-immunoprecipitation studies with the p.Arg693Trp variant protein showed reduced dimer formation compared to wild type (Singer et al. 2014). The p.Arg693Trp variant protein was also found to be more potent at activating inflammasome complexes compared to wild type protein (Khare et al. 2012).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R693Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -0.172
• Publications: 16 publications found

Genes affected

NLRP7 (HGNC:22947): (NLR family pyrin domain containing 7) This gene encodes a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family. It has an N-terminal pyrin domain, followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NLRP proteins are implicated in the activation of proinflammatory caspases through multiprotein complexes called inflammasomes. This gene may act as a feedback regulator of caspase-1-dependent interleukin 1-beta secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

NCR1 (HGNC:6731): (natural cytotoxicity triggering receptor 1) Predicted to be involved in cellular defense response; regulation of natural killer cell mediated cytotoxicity; and signal transduction. Predicted to act upstream of or within defense response to virus and detection of virus. Predicted to be located in cell surface. Predicted to be part of SWI/SNF complex. Predicted to be active in plasma membrane. Biomarker of acquired immunodeficiency syndrome; anogenital venereal wart; hepatitis C; and lymphoproliferative syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000414696: Co-immunoprecipitation studies with the p.Arg693Trp variant protein showed reduced dimer formation compared to wild type (Singer et al. 2014). The p.Arg693Trp variant protein was also found to be more potent at activating inflammasome complexes compared to wild type protein (Khare et al. 2012).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-54938095-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1591.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 19-54938096-G-A is Pathogenic according to our data. Variant chr19-54938096-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1586.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127255.2. 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
	NLRP7	NM_001127255.2	MANE Select	c.2077C>T	p.Arg693Trp	missense	Exon 5 of 11	NP_001120727.1	Q8WX94-3
	NLRP7	NM_001405531.1		c.2077C>T	p.Arg693Trp	missense	Exon 7 of 13	NP_001392460.1	Q8WX94-3
	NLRP7	NM_139176.4		c.1993C>T	p.Arg665Trp	missense	Exon 5 of 11	NP_631915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.2077C>T	p.Arg693Trp	missense	Exon 5 of 11	ENSP00000468706.1	Q8WX94-3
	NLRP7	ENST00000588756.5	TSL:1	c.2077C>T	p.Arg693Trp	missense	Exon 7 of 13	ENSP00000467123.1	Q8WX94-3
	NLRP7	ENST00000340844.6	TSL:1	c.2077C>T	p.Arg693Trp	missense	Exon 5 of 10	ENSP00000339491.2	Q8WX94-1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152096 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: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000274 AC: 69 AN: 251496 AF XY: 0.000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000198 AC: 290 AN: 1461830 Hom.: 1 Cov.: 33 AF XY: 0.000190 AC XY: 138 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00225 AC: 120 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000138 AC: 154 AN: 1111960

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

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

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hydatidiform mole, recurrent, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.39	N
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.17
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.64
MPC		0.89
ClinPred		0.76	D
GERP RS		-0.15
Varity_R		0.22
gMVP		0.46
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs104895506; hg19: chr19-55449464; COSMIC: COSV60172954; COSMIC: COSV60172954;