rs104895526

Positions:

• chr19-54936405-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127255.2(NLRP7):​c.2156C>T​(p.Ala719Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,074 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A719A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 3.01

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053436667).
• BP6: Variant 19-54936405-G-A is Benign according to our data. Variant chr19-54936405-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97747.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}. Variant chr19-54936405-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00115 (1685/1461766) while in subpopulation MID AF= 0.017 (98/5768). AF 95% confidence interval is 0.0143. There are 5 homozygotes in gnomad4_exome. There are 801 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.2156C>T	p.Ala719Val	missense_variant	6/11		NP_001120727.1
NLRP7	NM_001405531.1	c.2156C>T	p.Ala719Val	missense_variant	8/13		NP_001392460.1
NLRP7	NM_139176.4	c.2072C>T	p.Ala691Val	missense_variant	6/11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.2156C>T	p.Ala719Val	missense_variant	6/11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00105 AC: 264 AN: 251356 Hom.: 1 AF XY: 0.00107 AC XY: 146 AN XY: 135842

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00115 AC: 1685 AN: 1461766 Hom.: 5 Cov.: 34 AF XY: 0.00110 AC XY: 801 AN XY: 727184

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74472

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00132 Hom.: 2

Bravo AF: 0.000937

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00119 AC: 144

EpiCase AF: 0.00131

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NLRP7: BP4, BS1 -

Hydatidiform mole, recurrent, 1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;.;T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.070	N
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.053	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;L;L;L
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;.;.;.;.
Sift4G	Benign	0.095	T;T;T;T;T
Polyphen		0.95	P;D;P;.;.
Vest4		0.52
MVP		0.52
MPC		0.39
ClinPred		0.034	T
GERP RS		0.90
Varity_R		0.11
gMVP		0.18

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: rs104895526; hg19: chr19-55447773; COSMIC: COSV60176018; COSMIC: COSV60176018;