3-37058868-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006309.4(LRRFIP2):c.1792T>G(p.Cys598Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,918 control chromosomes in the GnomAD database, including 53 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: LRRFIP2 NM_006309.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.421

Genes affected

LRRFIP2 (HGNC:6703): (LRR binding FLII interacting protein 2) The protein encoded by this gene, along with MYD88, binds to the cytosolic tail of toll-like receptor 4 (TLR4), which results in activation of nuclear factor kappa B signaling. The ubiquitin-like protein FAT10 prevents the interaction of the encoded protein and TLR4, thereby inactivating the nuclear factor kappa B signaling pathway. In addition, this protein can downregulate the NLRP3 inflammasome by recruiting the caspase-1 inhibitor Flightless-I to the inflammasome complex. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028328896).
• BP6: Variant 3-37058868-A-C is Benign according to our data. Variant chr3-37058868-A-C is described in ClinVar as [Benign]. Clinvar id is 791917.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1779/152128) while in subpopulation AFR AF= 0.0399 (1656/41476). AF 95% confidence interval is 0.0383. There are 22 homozygotes in gnomad4. There are 818 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRFIP2	NM_006309.4	c.1792T>G	p.Cys598Gly	missense_variant	25/28	ENST00000336686.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRFIP2	ENST00000336686.9	c.1792T>G	p.Cys598Gly	missense_variant	25/28	1	NM_006309.4

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1778 AN: 152010 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00319 AC: 801 AN: 251178 Hom.: 13 AF XY: 0.00228 AC XY: 310 AN XY: 135728

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00120 AC: 1754 AN: 1461790 Hom.: 31 Cov.: 31 AF XY: 0.000980 AC XY: 713 AN XY: 727194

Gnomad4 AFR exome AF: 0.0418

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152128 Hom.: 22 Cov.: 32 AF XY: 0.0110 AC XY: 818 AN XY: 74358

Gnomad4 AFR AF: 0.0399

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00220 Hom.: 8

Bravo AF: 0.0133

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00386 AC: 469

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	16
Dann	Benign	0.89
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.52	T;T;.;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.44	T;T;T;T;T
Polyphen		0.0010	B;B;B;.;B
Vest4		0.26
MVP		0.31
ClinPred		0.0071	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.31

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: rs58970254; hg19: chr3-37100359; COSMIC: COSV99068715; COSMIC: COSV99068715;