7-100358843-G-A

Position:

• chr7-100358843-G-A

Variant summary

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

The NM_178238.4(PILRB):​c.218G>A​(p.Arg73Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PILRB NM_178238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.404

Genes affected

PILRB (HGNC:18297): (paired immunoglobin like type 2 receptor beta) The paired immunoglobin-like type 2 receptors consist of highly related activating and inhibitory receptors that are involved in the regulation of many aspects of the immune system. The paired immunoglobulin-like receptor genes are located in a tandem head-to-tail orientation on chromosome 7. This gene encodes the activating member of the receptor pair and contains a truncated cytoplasmic tail relative to its inhibitory counterpart (PILRA), that has a long cytoplasmic tail with immunoreceptor tyrosine-based inhibitory (ITIM) motifs. This gene is thought to have arisen from a duplication of the inhibitory PILRA gene and evolved to acquire its activating function. [provided by RefSeq, Jun 2013]

STAG3L5P-PVRIG2P-PILRB (HGNC:):

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=0.100023955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PILRB	NM_178238.4	c.218G>A	p.Arg73Gln	missense_variant	2/4	ENST00000609309.3	NP_839956.1
PILRB	NM_001371931.2	c.218G>A	p.Arg73Gln	missense_variant	2/5		NP_001358860.1
STAG3L5P-PVRIG2P-PILRB	NR_036569.1	n.2763G>A		non_coding_transcript_exon_variant	16/18
STAG3L5P-PVRIG2P-PILRB	NR_036570.1	n.2143-56G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PILRB	ENST00000609309.3	c.218G>A	p.Arg73Gln	missense_variant	2/4	1	NM_178238.4	ENSP00000477365.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251456 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 88 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74284

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000164

EpiControl AF: 0.000237

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

Aug 14, 2023

The c.218G>A (p.R73Q) alteration is located in exon 2 (coding exon 2) of the PILRB gene. This alteration results from a G to A substitution at nucleotide position 218, causing the arginine (R) at amino acid position 73 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.;.;.;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.81	.;.;.;.;T;T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;M
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.8	N;N;N;N;N;.;N;.
REVEL	Benign	0.088
Sift	Benign	0.28	T;T;T;T;T;.;T;.
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;.;D
Vest4		0.17
MutPred		0.67		Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);Loss of methylation at R73 (P = 0.0116);
MVP		0.099
ClinPred		0.10	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs747431707; hg19: chr7-99956466;