rs104895509

Variant names:

• chr19-54941461-C-T
• rs104895509
• ENST00000588756.5:c.251G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001127255.2(NLRP7):​c.251G>A​(p.Cys84Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,599,190 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.373

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006420046).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000366 (55/150442) while in subpopulation EAS AF= 0.00552 (28/5072). AF 95% confidence interval is 0.00392. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.251G>A	p.Cys84Tyr	missense_variant	Exon 2 of 11		NP_001120727.1
NLRP7	NM_001405531.1	c.251G>A	p.Cys84Tyr	missense_variant	Exon 4 of 13		NP_001392460.1
NLRP7	NM_139176.4	c.251G>A	p.Cys84Tyr	missense_variant	Exon 2 of 11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.251G>A	p.Cys84Tyr	missense_variant	Exon 2 of 11	1		ENSP00000468706.1

Frequencies

GnomAD3 genomes AF: 0.000359 AC: 54 AN: 150374 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00570

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00243

GnomAD3 exomes AF: 0.000453 AC: 114 AN: 251424 Hom.: 2 AF XY: 0.000456 AC XY: 62 AN XY: 135892

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00555

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000159 AC: 231 AN: 1448748 Hom.: 3 Cov.: 34 AF XY: 0.000147 AC XY: 106 AN XY: 720592

Gnomad4 AFR exome AF: 0.0000906

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00331

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000366 AC: 55 AN: 150442 Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 22 AN XY: 73362

Gnomad4 AFR AF: 0.000316

Gnomad4 AMR AF: 0.000399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00552

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00338

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 09, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.43
DEOGEN2	Benign	0.13	T;.;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0063	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0064	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;L;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D;.;.;.;.
Sift4G	Uncertain	0.043	D;T;D;D;D;.
Polyphen		0.59	P;B;P;.;.;.
Vest4		0.17
MVP		0.28
MPC		0.51
ClinPred		0.031	T
GERP RS		0.24
Varity_R		0.25
gMVP		0.88

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: rs104895509; hg19: chr19-55452829; COSMIC: COSV60172292; COSMIC: COSV60172292;