19-54587200-G-A

Variant names:

• chr19-54587200-G-A
• rs2241524
• NM_001130917.3:c.1307-1G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_001130917.3(LILRA2):​c.1307-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,466 control chromosomes in the GnomAD database, including 3,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.037 (403 hom., cov: 32)
  • Exomes 𝑓: 0.025 (3112 hom.)
• Consequence: LILRA2 NM_001130917.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.64
• Publications: 17 publications found

Genes affected

LILRA2 (HGNC:6603): (leukocyte immunoglobulin like receptor A2) This gene encodes a member of a family of immunoreceptors that are expressed predominantly on monocytes and B cells, and at lower levels on dendritic cells and natural killer cells. The encoded protein is an activating receptor that inhibits dendritic cell differentiation and antigen presentation and suppresses innate immune response. Alternatively spliced transcript variants encoding different isoforms have been found. This gene is located in a cluster of related genes on chromosome 19 and there is a pseudogene for this gene on chromosome 3. [provided by RefSeq, Mar 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 2.126033 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.5, offset of 9, new splice context is: tctttgtccaacatccctAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130917.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LILRA2	NM_001130917.3	MANE Select	c.1307-1G>A		splice_acceptor intron	N/A	NP_001124389.2
	LILRA2	NM_001290271.2		c.*42-1G>A		splice_acceptor intron	N/A	NP_001277200.1
	LILRA2	NM_006866.4		c.1256-1G>A		splice_acceptor intron	N/A	NP_006857.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LILRA2	ENST00000391738.8	TSL:1 MANE Select	c.1307-1G>A		splice_acceptor intron	N/A	ENSP00000375618.3
	LILRA2	ENST00000251376.7	TSL:1	c.1256-1G>A		splice_acceptor intron	N/A	ENSP00000251376.3
	LILRA2	ENST00000391737.3	TSL:1	c.1220-1G>A		splice_acceptor intron	N/A	ENSP00000375617.1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5609 AN: 152048 Hom.: 404 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.0345

GnomAD2 exomes AF: 0.0662 AC: 16402 AN: 247804 AF XY: 0.0579

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00965

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0248 AC: 36177 AN: 1461300 Hom.: 3112 Cov.: 32 AF XY: 0.0243 AC XY: 17630 AN XY: 726916

African (AFR) AF: 0.0281 AC: 940 AN: 33478

American (AMR) AF: 0.205 AC: 9155 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 290 AN: 26126

East Asian (EAS) AF: 0.299 AC: 11881 AN: 39684

South Asian (SAS) AF: 0.0377 AC: 3240 AN: 85928

European-Finnish (FIN) AF: 0.0153 AC: 817 AN: 53418

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5762

European-Non Finnish (NFE) AF: 0.00711 AC: 7903 AN: 1111832

Other (OTH) AF: 0.0308 AC: 1861 AN: 60352

GnomAD4 genome AF: 0.0370 AC: 5623 AN: 152166 Hom.: 403 Cov.: 32 AF XY: 0.0403 AC XY: 3001 AN XY: 74400

African (AFR) AF: 0.0294 AC: 1221 AN: 41508

American (AMR) AF: 0.114 AC: 1748 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.291 AC: 1505 AN: 5164

South Asian (SAS) AF: 0.0486 AC: 234 AN: 4814

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00906 AC: 616 AN: 67982

Other (OTH) AF: 0.0346 AC: 73 AN: 2110

Alfa AF: 0.0188 Hom.: 147

Bravo AF: 0.0487

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.0576 AC: 6994

EpiCase AF: 0.00889

EpiControl AF: 0.0108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.99	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.1
DANN	Benign	0.50
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0023	N
PhyloP100		-4.6
GERP RS		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.80		Position offset: 10
DS_AL_spliceai		0.76		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2241524; hg19: chr19-55098667; COSMIC: COSV52189668; COSMIC: COSV52189668;