19-55785798-T-G

Position:

• chr19-55785798-T-G

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.2929A>C​(p.Ile977Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,614,088 control chromosomes in the GnomAD database, including 91 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 0.0078 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (85 hom.)
• Consequence: NLRP11 NM_001394894.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.59

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=0.0045933723).
• BP6: Variant 19-55785798-T-G is Benign according to our data. Variant chr19-55785798-T-G is described in ClinVar as [Benign]. Clinvar id is 787573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP11	NM_001394894.2	c.2929A>C	p.Ile977Leu	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.2929A>C	p.Ile977Leu	missense_variant	10/10	1	NM_001394894.2	ENSP00000466285	P1
NLRP11	ENST00000592953.5	c.2632A>C	p.Ile878Leu	missense_variant	9/9	1		ENSP00000468196
NLRP11	ENST00000590409.5	c.*743A>C		3_prime_UTR_variant, NMD_transcript_variant	12/12	1		ENSP00000466582
NLRP11	ENST00000589824.6	c.2767A>C	p.Ile923Leu	missense_variant	8/8	5		ENSP00000468082

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1183 AN: 152212 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00683 AC: 1718 AN: 251386 Hom.: 4 AF XY: 0.00700 AC XY: 951 AN XY: 135866

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00984

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00976 AC: 14269 AN: 1461758 Hom.: 85 Cov.: 32 AF XY: 0.00958 AC XY: 6968 AN XY: 727192

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00735

GnomAD4 genome AF: 0.00776 AC: 1182 AN: 152330 Hom.: 6 Cov.: 32 AF XY: 0.00781 AC XY: 582 AN XY: 74490

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.0105 Hom.: 12

Bravo AF: 0.00636

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00724 AC: 879

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0100

EpiControl AF: 0.00948

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.14
DANN	Benign	0.39
DEOGEN2	Benign	0.0051	.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.39	T;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.41	B;.;B
Vest4		0.16
MVP		0.25
ClinPred		0.0025	T
GERP RS		-2.8
Varity_R		0.053
gMVP		0.058

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: rs116820715; hg19: chr19-56297164; COSMIC: COSV105277001;