NM_001130917.3:c.1307-1G>C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001130917.3(LILRA2):​c.1307-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,608,366 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (0 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_pathogenic. The variant received 6 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 9, offset of 9, new splice context is: tctttgtccaccatccctAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Variant has high frequency in the SAS (0.0387) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).

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>C		splice_acceptor intron	N/A	NP_001124389.2
	LILRA2	NM_001290271.2		c.*42-1G>C		splice_acceptor intron	N/A	NP_001277200.1
	LILRA2	NM_006866.4		c.1256-1G>C		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>C		splice_acceptor intron	N/A	ENSP00000375618.3
	LILRA2	ENST00000251376.7	TSL:1	c.1256-1G>C		splice_acceptor intron	N/A	ENSP00000251376.3
	LILRA2	ENST00000391737.3	TSL:1	c.1220-1G>C		splice_acceptor intron	N/A	ENSP00000375617.1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00792

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00188 AC: 465 AN: 247804 AF XY: 0.00233

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00301 AC: 4385 AN: 1456214 Hom.: 0 Cov.: 32 AF XY: 0.00426 AC XY: 3085 AN XY: 723718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000209 AC: 7 AN: 33462

American (AMR) AF: 0.00148 AC: 66 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00666 AC: 264 AN: 39626

South Asian (SAS) AF: 0.0398 AC: 3283 AN: 82458

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.00881 AC: 50 AN: 5676

European-Non Finnish (NFE) AF: 0.000483 AC: 536 AN: 1110762

Other (OTH) AF: 0.00292 AC: 175 AN: 60024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74384

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000313 AC: 13 AN: 41520

American (AMR) AF: 0.00177 AC: 27 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00814 AC: 42 AN: 5162

South Asian (SAS) AF: 0.0705 AC: 337 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000137 Hom.: 147

ExAC AF: 0.00829 AC: 1006

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.93	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.81
DANN	Benign	0.46
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.00014	N
PhyloP100		-4.6
GERP RS		-2.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.83		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;