rs104895502

Variant names:

• chr19-54938095-C-G
• rs104895502
• NM_001127255.2:c.2078G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-54938095-C-G
• chr19-54938095-C-T
• chr19-54938095-C-A

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.2078G>C​(p.Arg693Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004175321: Genome-wide methylation studies on molar tissue from two sisters homozygous for the variant demonstrated aberrant methylation at maternal differentially methylated regions compared to non-molar normal placental tissue (PMID:26544189) (PS3_Supporting).". 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -0.00300
• Publications: 15 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: SCV004175321: Genome-wide methylation studies on molar tissue from two sisters homozygous for the variant demonstrated aberrant methylation at maternal differentially methylated regions compared to non-molar normal placental tissue (PMID: 26544189) (PS3_Supporting).
• 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 19-54938095-C-G is Pathogenic according to our data. Variant chr19-54938095-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1587.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.2078G>C	p.Arg693Pro	missense	Exon 5 of 11	NP_001120727.1	Q8WX94-3
	NLRP7	NM_001405531.1		c.2078G>C	p.Arg693Pro	missense	Exon 7 of 13	NP_001392460.1	Q8WX94-3
	NLRP7	NM_139176.4		c.1994G>C	p.Arg665Pro	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.2078G>C	p.Arg693Pro	missense	Exon 5 of 11	ENSP00000468706.1	Q8WX94-3
	NLRP7	ENST00000588756.5	TSL:1	c.2078G>C	p.Arg693Pro	missense	Exon 7 of 13	ENSP00000467123.1	Q8WX94-3
	NLRP7	ENST00000340844.6	TSL:1	c.2078G>C	p.Arg693Pro	missense	Exon 5 of 10	ENSP00000339491.2	Q8WX94-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152030 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: 0.0000477 AC: 12 AN: 251494 AF XY: 0.0000441

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: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000568 AC: 83 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.0000578 AC XY: 42 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111994

Other (OTH) AF: 0.000116 AC: 7 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15230

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	Pathogenic	0.84
BayesDel_addAF	Benign	0.0064	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.0073	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.0030
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.59
MPC		1.0
ClinPred		0.54	D
GERP RS		1.1
Varity_R		0.73
gMVP		0.71
Mutation Taster		=0/100	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: rs104895502; hg19: chr19-55449463;