rs104895526

Variant names:

• chr19-54936405-G-A
• rs104895526
• NM_001127255.2:c.2156C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-54936405-G-A
• chr19-54936405-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A719T) has been classified as Uncertain significance.

• 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
• Publications: 13 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001127255.2
• 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 VariationId is 97747.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 801 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	NM_001127255.2	MANE Select	c.2156C>T	p.Ala719Val	missense	Exon 6 of 11	NP_001120727.1
	NLRP7	NM_001405531.1		c.2156C>T	p.Ala719Val	missense	Exon 8 of 13	NP_001392460.1
	NLRP7	NM_139176.4		c.2072C>T	p.Ala691Val	missense	Exon 6 of 11	NP_631915.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.2156C>T	p.Ala719Val	missense	Exon 6 of 11	ENSP00000468706.1
	NLRP7	ENST00000588756.5	TSL:1	c.2156C>T	p.Ala719Val	missense	Exon 8 of 13	ENSP00000467123.1
	NLRP7	ENST00000340844.6	TSL:1	c.2156C>T	p.Ala719Val	missense	Exon 6 of 10	ENSP00000339491.2

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

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251356 AF XY: 0.00107

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 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

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86254

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53420

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.00126 AC: 1405 AN: 1111898

Other (OTH) AF: 0.00113 AC: 68 AN: 60388

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

African (AFR) AF: 0.000553 AC: 23 AN: 41576

American (AMR) AF: 0.000655 AC: 10 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68042

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00133 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Hydatidiform mole, recurrent, 1 (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.0
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.095	T
Polyphen		0.95	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
Mutation Taster		=97/3	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: rs104895526; hg19: chr19-55447773; COSMIC: COSV60176018; COSMIC: COSV60176018;