rs749072

Variant names:

• chr3-37054533-T-C
• rs749072
• NM_006309.4:c.1951-18A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006309.4(LRRFIP2):​c.1951-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,570,158 control chromosomes in the GnomAD database, including 64,235 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.27 (5983 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58252 hom.)
• Consequence: LRRFIP2 NM_006309.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.09
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006309.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRFIP2	NM_006309.4	MANE Select	c.1951-18A>G		intron	N/A	NP_006300.1	Q9Y608-1
	LRRFIP2	NM_001348297.1		c.1648-18A>G		intron	N/A	NP_001335226.1
	LRRFIP2	NM_001348298.1		c.1438-18A>G		intron	N/A	NP_001335227.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRFIP2	ENST00000336686.9	TSL:1 MANE Select	c.1951-18A>G		intron	N/A	ENSP00000338727.4	Q9Y608-1
	LRRFIP2	ENST00000354379.8	TSL:1	c.988-18A>G		intron	N/A	ENSP00000346349.4	Q9Y608-2
	LRRFIP2	ENST00000460646.5	TSL:1	n.1795-18A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40841 AN: 151948 Hom.: 5985 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.321 AC: 79649 AN: 247830 AF XY: 0.323

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.615

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.278 AC: 393663 AN: 1418092 Hom.: 58252 Cov.: 24 AF XY: 0.281 AC XY: 199127 AN XY: 707622

African (AFR) AF: 0.212 AC: 6866 AN: 32454

American (AMR) AF: 0.346 AC: 15182 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9103 AN: 25790

East Asian (EAS) AF: 0.577 AC: 22794 AN: 39524

South Asian (SAS) AF: 0.400 AC: 33817 AN: 84500

European-Finnish (FIN) AF: 0.289 AC: 15378 AN: 53302

Middle Eastern (MID) AF: 0.377 AC: 2139 AN: 5670

European-Non Finnish (NFE) AF: 0.252 AC: 270633 AN: 1073946

Other (OTH) AF: 0.301 AC: 17751 AN: 58980

GnomAD4 genome AF: 0.269 AC: 40864 AN: 152066 Hom.: 5983 Cov.: 32 AF XY: 0.275 AC XY: 20437 AN XY: 74334

African (AFR) AF: 0.214 AC: 8889 AN: 41468

American (AMR) AF: 0.297 AC: 4530 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3468

East Asian (EAS) AF: 0.595 AC: 3078 AN: 5174

South Asian (SAS) AF: 0.408 AC: 1966 AN: 4824

European-Finnish (FIN) AF: 0.285 AC: 3003 AN: 10542

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17258 AN: 68002

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.264 Hom.: 4082

Bravo AF: 0.271

Asia WGS AF: 0.485 AC: 1683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.021
DANN	Benign	0.69
PhyloP100		-3.1
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs749072; hg19: chr3-37096024; COSMIC: COSV51614379; COSMIC: COSV51614379;