19-54939682-C-G

Variant names:

• chr19-54939682-C-G
• rs10418277
• ENST00000588756.5:c.1137G>C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 97715.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, not_provided=1}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP7	NM_001127255.2	c.1137G>C	p.Lys379Asn	missense_variant	Exon 4 of 11		NP_001120727.1
NLRP7	NM_001405531.1	c.1137G>C	p.Lys379Asn	missense_variant	Exon 6 of 13		NP_001392460.1
NLRP7	NM_139176.4	c.1137G>C	p.Lys379Asn	missense_variant	Exon 4 of 11		NP_631915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP7	ENST00000592784.6	c.1137G>C	p.Lys379Asn	missense_variant	Exon 4 of 11	1		ENSP00000468706.1

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

GnomAD3 exomes AF: 0.00501 AC: 1248 AN: 249060 Hom.: 20 AF XY: 0.00483 AC XY: 652 AN XY: 135116

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 SAS exome AF: 0.000621

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

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0161

Gnomad4 SAS exome AF: 0.000650

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.00196

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

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00857

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0441

Gnomad4 NFE AF: 0.000854

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00179 Hom.: 322

ExAC AF: 0.00446 AC: 541

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hydatidiform mole, recurrent, 1 Uncertain:1 Other:1

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NLRP7: BP4, BS1, BS2 -

Malignant tumor of prostate Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0075	N
MetaRNN	Benign	0.0071	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;L;L;L;L
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D;D;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.057	T;T;.;.;.
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0090	B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs10418277; hg19: chr19-55451050;