chr19-54941461-C-T

Variant names:

• chr19-54941461-C-T
• rs104895509
• NM_001127255.2:c.251G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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
• Publications: 5 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]

NLRP7 Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• complete hydatidiform mole

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.251G>A	p.Cys84Tyr	missense	Exon 2 of 11	NP_001120727.1	Q8WX94-3
	NLRP7	NM_001405531.1		c.251G>A	p.Cys84Tyr	missense	Exon 4 of 13	NP_001392460.1	Q8WX94-3
	NLRP7	NM_139176.4		c.251G>A	p.Cys84Tyr	missense	Exon 2 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.251G>A	p.Cys84Tyr	missense	Exon 2 of 11	ENSP00000468706.1	Q8WX94-3
	NLRP7	ENST00000588756.5	TSL:1	c.251G>A	p.Cys84Tyr	missense	Exon 4 of 13	ENSP00000467123.1	Q8WX94-3
	NLRP7	ENST00000340844.6	TSL:1	c.251G>A	p.Cys84Tyr	missense	Exon 2 of 10	ENSP00000339491.2	Q8WX94-1

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

GnomAD2 exomes AF: 0.000453 AC: 114 AN: 251424 AF XY: 0.000456

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 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

African (AFR) AF: 0.0000906 AC: 3 AN: 33114

American (AMR) AF: 0.0000451 AC: 2 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00331 AC: 129 AN: 38990

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103116

Other (OTH) AF: 0.00151 AC: 90 AN: 59518

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

African (AFR) AF: 0.000316 AC: 13 AN: 41120

American (AMR) AF: 0.000399 AC: 6 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00552 AC: 28 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67628

Other (OTH) AF: 0.00338 AC: 7 AN: 2070

Alfa AF: 0.000244 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.37
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.043	D
Polyphen		0.59	P
Vest4		0.17
MVP		0.28
MPC		0.51
ClinPred		0.031	T
GERP RS		0.24
PromoterAI		-0.041	Neutral
Varity_R		0.25
gMVP		0.88
Mutation Taster		=61/39	polymorphism

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