rs104895513

Variant names:

• chr19-54930497-A-C
• rs104895513
• NM_001127255.2:c.2810+2T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-54930497-A-C
• chr19-54930497-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_001127255.2(NLRP7):​c.2810+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000814 in 1,596,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: NLRP7 NM_001127255.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.67
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053949904 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	NM_001127255.2	MANE Select	c.2810+2T>G		splice_donor intron	N/A	NP_001120727.1
	NLRP7	NM_001405531.1		c.2810+2T>G		splice_donor intron	N/A	NP_001392460.1
	NLRP7	NM_139176.4		c.2726+2T>G		splice_donor intron	N/A	NP_631915.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.2810+2T>G		splice_donor intron	N/A	ENSP00000468706.1
	NLRP7	ENST00000588756.5	TSL:1	c.2810+2T>G		splice_donor intron	N/A	ENSP00000467123.1
	NLRP7	ENST00000340844.6	TSL:1	c.2810+2T>G		splice_donor intron	N/A	ENSP00000339491.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251018 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1444414 Hom.: 0 Cov.: 27 AF XY: 0.00000417 AC XY: 3 AN XY: 719878

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.000224 AC: 10 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096314

Other (OTH) AF: 0.0000167 AC: 1 AN: 59754

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152060 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Benign	0.67
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.15	N
PhyloP100		1.7
GERP RS		2.1
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104895513; hg19: chr19-55441865;