19-54941461-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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 -12 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.
• 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;