19-55785653-G-A

Position:

• chr19-55785653-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001394894.2(NLRP11):​c.3074C>T​(p.Ser1025Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 1,613,840 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (70 hom.)
• Consequence: NLRP11 NM_001394894.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650

Genes affected

NLRP11 (HGNC:22945): (NLR family pyrin domain containing 11) This gene is a member of the the NOD-like receptor protein (NLRP) gene family and encodes a protein with an N-terminal pyrin death (PYD) domain and nucleoside triphosphate hydrolase (NACHT) domain and a C-terminal leucine-rich repeats (LRR) region. This gene has been shown to regulate caspases in the proinflammatory signal transduction pathway and, based on studies of other members of the NLRP gene family with similar domain structure, is predicted to form part of the multiprotein inflammasome complex. Alternative splicing produces multiple transcript variants encoding distince isoforms. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074005127).
• BP6: Variant 19-55785653-G-A is Benign according to our data. Variant chr19-55785653-G-A is described in ClinVar as [Benign]. Clinvar id is 789353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP11	NM_001394894.2	c.3074C>T	p.Ser1025Leu	missense_variant	10/10	ENST00000589093.6	NP_001381823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP11	ENST00000589093.6	c.3074C>T	p.Ser1025Leu	missense_variant	10/10	1	NM_001394894.2	ENSP00000466285	P1
NLRP11	ENST00000592953.5	c.2777C>T	p.Ser926Leu	missense_variant	9/9	1		ENSP00000468196
NLRP11	ENST00000590409.5	c.*888C>T		3_prime_UTR_variant, NMD_transcript_variant	12/12	1		ENSP00000466582
NLRP11	ENST00000589824.6	c.2912C>T	p.Ser971Leu	missense_variant	8/8	5		ENSP00000468082

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1054 AN: 152162 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00673 AC: 1690 AN: 251286 Hom.: 13 AF XY: 0.00705 AC XY: 957 AN XY: 135840

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00865 AC: 12648 AN: 1461560 Hom.: 70 Cov.: 32 AF XY: 0.00843 AC XY: 6131 AN XY: 727100

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00637

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00262

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00745

GnomAD4 genome AF: 0.00692 AC: 1054 AN: 152280 Hom.: 9 Cov.: 32 AF XY: 0.00625 AC XY: 465 AN XY: 74448

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0107 Hom.: 11

Bravo AF: 0.00707

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00676 AC: 821

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.9
DANN	Benign	0.96
DEOGEN2	Benign	0.0042	.;.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;P
Vest4		0.10
MVP		0.70
ClinPred		0.0044	T
GERP RS		-1.5
Varity_R		0.049
gMVP		0.066

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: rs11671248; hg19: chr19-56297019; COSMIC: COSV105276913;