19-54250896-C-T

Position:

• chr19-54250896-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001081442.3(LILRB5):​c.1666G>A​(p.Ala556Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,577,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: LILRB5 NM_001081442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

LILRB5 (HGNC:6609): (leukocyte immunoglobulin like receptor B5) This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19q13.4. The encoded protein belongs to the subfamily B class of LIR receptors which contain two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Several other LIR subfamily B receptors are expressed on immune cells where they bind to MHC class I molecules on antigen-presenting cells and inhibit stimulation of an immune response. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07946181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LILRB5	NM_001081442.3	c.1666G>A	p.Ala556Thr	missense_variant	13/13	ENST00000449561.3	NP_001074911.2
LILRB5	NM_001304457.3	c.1876G>A	p.Ala626Thr	missense_variant	13/13		NP_001291386.2
LILRB5	NM_006840.5	c.1663G>A	p.Ala555Thr	missense_variant	13/13		NP_006831.2
LILRB5	NM_001081443.3	c.1366G>A	p.Ala456Thr	missense_variant	12/12		NP_001074912.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LILRB5	ENST00000449561.3	c.1666G>A	p.Ala556Thr	missense_variant	13/13	1	NM_001081442.3	ENSP00000406478	P4

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 36 AN: 136980 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000417

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000482

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.000291

Gnomad OTH AF: 0.000534

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251232 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135840

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000206 AC: 297 AN: 1440582 Hom.: 0 Cov.: 36 AF XY: 0.000219 AC XY: 157 AN XY: 716706

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000340

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000409

GnomAD4 genome AF: 0.000263 AC: 36 AN: 137070 Hom.: 0 Cov.: 26 AF XY: 0.000229 AC XY: 15 AN XY: 65478

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000417

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000482

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000291

Gnomad4 OTH AF: 0.000529

Alfa AF: 0.000171 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

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

Apr 07, 2022

The c.1666G>A (p.A556T) alteration is located in exon 13 (coding exon 13) of the LILRB5 gene. This alteration results from a G to A substitution at nucleotide position 1666, causing the alanine (A) at amino acid position 556 to be replaced by a threonine (T). 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	0.27
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.012	N
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.049
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Vest4		0.27
MVP		0.12
MPC		0.26
ClinPred		0.13	T
GERP RS		-0.70
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112549096; hg19: chr19-54754760; COSMIC: COSV60260909; COSMIC: COSV60260909;