rs10418277

Variant names:

• chr19-54939682-C-G
• rs10418277
• NM_001127255.2:c.1137G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-54939682-C-G
• chr19-54939682-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127255.2(NLRP7):​c.1137G>C​(p.Lys379Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,612,818 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K379K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (55 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: -6.88
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070764422).
• BP6: Variant 19-54939682-C-G is Benign according to our data. Variant chr19-54939682-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97715.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00389 (591/152008) while in subpopulation EAS AF = 0.00857 (44/5132). AF 95% confidence interval is 0.00656. There are 12 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.1137G>C	p.Lys379Asn	missense	Exon 4 of 11	NP_001120727.1	Q8WX94-3
	NLRP7	NM_001405531.1		c.1137G>C	p.Lys379Asn	missense	Exon 6 of 13	NP_001392460.1	Q8WX94-3
	NLRP7	NM_139176.4		c.1137G>C	p.Lys379Asn	missense	Exon 4 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.1137G>C	p.Lys379Asn	missense	Exon 4 of 11	ENSP00000468706.1	Q8WX94-3
	NLRP7	ENST00000588756.5	TSL:1	c.1137G>C	p.Lys379Asn	missense	Exon 6 of 13	ENSP00000467123.1	Q8WX94-3
	NLRP7	ENST00000340844.6	TSL:1	c.1137G>C	p.Lys379Asn	missense	Exon 4 of 10	ENSP00000339491.2	Q8WX94-1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 591 AN: 151890 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00855

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00501 AC: 1248 AN: 249060 AF XY: 0.00483

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00225 AC: 3290 AN: 1460810 Hom.: 55 Cov.: 74 AF XY: 0.00226 AC XY: 1639 AN XY: 726734

African (AFR) AF: 0.0000897 AC: 3 AN: 33444

American (AMR) AF: 0.000246 AC: 11 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26130

East Asian (EAS) AF: 0.0161 AC: 638 AN: 39700

South Asian (SAS) AF: 0.000650 AC: 56 AN: 86214

European-Finnish (FIN) AF: 0.0379 AC: 2017 AN: 53216

Middle Eastern (MID) AF: 0.000387 AC: 2 AN: 5170

European-Non Finnish (NFE) AF: 0.000358 AC: 398 AN: 1111932

Other (OTH) AF: 0.00196 AC: 118 AN: 60320

GnomAD4 genome AF: 0.00389 AC: 591 AN: 152008 Hom.: 12 Cov.: 31 AF XY: 0.00585 AC XY: 435 AN XY: 74306

African (AFR) AF: 0.0000723 AC: 3 AN: 41484

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00857 AC: 44 AN: 5132

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4808

European-Finnish (FIN) AF: 0.0441 AC: 467 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000854 AC: 58 AN: 67952

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00115 Hom.: 426

ExAC AF: 0.00446 AC: 541

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0060
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0075	N
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PhyloP100		-6.9
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.12
Sift	Benign	0.057	T
Sift4G	Benign	0.29	T
Polyphen		0.0090	B
Vest4		0.47
MVP		0.12
MPC		0.29
ClinPred		0.0064	T
GERP RS		-2.5
Varity_R		0.11
gMVP		0.64
Mutation Taster		=99/1	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: rs10418277; hg19: chr19-55451050;