3-37102931-A-G

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.866T>C(p.Leu289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,558,856 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (4 hom.)
• Consequence: LRRFIP2 NM_006309.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.46

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=0.003613174).
• BP6: Variant 3-37102931-A-G is Benign according to our data. Variant chr3-37102931-A-G is described in ClinVar as [Benign]. Clinvar id is 775853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0049 (746/152232) while in subpopulation AFR AF= 0.0171 (711/41536). AF 95% confidence interval is 0.0161. There are 6 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRFIP2	NM_006309.4	c.866T>C	p.Leu289Ser	missense_variant	15/28	ENST00000336686.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRFIP2	ENST00000336686.9	c.866T>C	p.Leu289Ser	missense_variant	15/28	1	NM_006309.4

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 745 AN: 152114 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00128 AC: 219 AN: 171192 Hom.: 0 AF XY: 0.000979 AC XY: 88 AN XY: 89896

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000145

Gnomad OTH exome AF: 0.000853

GnomAD4 exome AF: 0.000474 AC: 667 AN: 1406624 Hom.: 4 Cov.: 30 AF XY: 0.000383 AC XY: 266 AN XY: 694360

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000752

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000120

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152232 Hom.: 6 Cov.: 30 AF XY: 0.00456 AC XY: 339 AN XY: 74420

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000814 Hom.: 0

Bravo AF: 0.00557

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00108 AC: 125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	0.88	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.090
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.074	T
Polyphen		0.0060	B
Vest4		0.28
MVP		0.43
ClinPred		0.045	T
GERP RS		2.6
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs75968372; hg19: chr3-37144422;