19-54574304-A-C

Position:

• chr19-54574304-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001130917.3(LILRA2):​c.74A>C​(p.His25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H25L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.46 (0 hom., cov: 44)
  • Exomes 𝑓: 0.24 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LILRA2 NM_001130917.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.946

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]

LILRA2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03821376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LILRA2	NM_001130917.3	c.74A>C	p.His25Pro	missense_variant	3/8	ENST00000391738.8	NP_001124389.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LILRA2	ENST00000391738.8	c.74A>C	p.His25Pro	missense_variant	3/8	1	NM_001130917.3	ENSP00000375618.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 60562 AN: 131452 Hom.: 0 Cov.: 44 FAILED QC

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.494

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.483

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.472

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251058 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.241 AC: 151390 AN: 629306 Hom.: 0 Cov.: 105 AF XY: 0.247 AC XY: 79581 AN XY: 322198

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.0715

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.461 AC: 60604 AN: 131554 Hom.: 0 Cov.: 44 AF XY: 0.459 AC XY: 29322 AN XY: 63920

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.289

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.472

Alfa AF: 0.0000317 Hom.: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.74A>C (p.H25P) alteration is located in exon 3 (coding exon 3) of the LILRA2 gene. This alteration results from a A to C substitution at nucleotide position 74, causing the histidine (H) at amino acid position 25 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.80
DANN	Benign	0.66
DEOGEN2	Benign	0.0024	T;.;.;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00018	N
LIST_S2	Benign	0.0094	T;.;.;.;T;.
M_CAP	Benign	0.00060	T
MetaRNN	Benign	0.038	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	1.6	N;N;N;N;N;.
REVEL	Benign	0.042
Sift	Benign	0.23	T;T;T;T;T;.
Sift4G	Benign	0.27	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;.
Vest4		0.062, 0.065, 0.068, 0.061, 0.066
MutPred		0.32		Gain of glycosylation at H25 (P = 0.0271);Gain of glycosylation at H25 (P = 0.0271);Gain of glycosylation at H25 (P = 0.0271);Gain of glycosylation at H25 (P = 0.0271);.;Gain of glycosylation at H25 (P = 0.0271);
MVP		0.12
MPC		0.019
ClinPred		0.063	T
GERP RS		0.12
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1834697; hg19: chr19-55085771;