chr7-100397887-C-T

Variant names:

• chr7-100397887-C-T
• rs145267648
• NM_013439.3:c.682C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_013439.3(PILRA):​c.682C>T​(p.Arg228Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R228Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PILRA NM_013439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.257
• Publications: 2 publications found

Genes affected

PILRA (HGNC:20396): (paired immunoglobin like type 2 receptor alpha) Cell signaling pathways rely on a dynamic interaction between activating and inhibiting processes. SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the regulation of several cell signaling pathways. Two types of inhibitory receptor superfamily members are immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors and their non-ITIM-bearing, activating counterparts. Control of cell signaling via SHP-1 is thought to occur through a balance between PILRalpha-mediated inhibition and PILRbeta-mediated activation. These paired immunoglobulin-like receptor genes are located in a tandem head-to-tail orientation on chromosome 7. This particular gene encodes the ITIM-bearing member of the receptor pair, which functions in the inhibitory role. Alternative splicing has been observed at this locus and three variants, each encoding a distinct isoform, are described. [provided by RefSeq, Jul 2008]

ENSG00000289690 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10436025).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013439.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PILRA	NM_013439.3	MANE Select	c.682C>T	p.Arg228Trp	missense	Exon 4 of 7	NP_038467.2
	PILRA	NM_178272.2		c.463C>T	p.Arg155Trp	missense	Exon 3 of 6	NP_840056.1	Q9UKJ1-3
	PILRA	NM_178273.2		c.455-1404C>T		intron	N/A	NP_840057.1	Q9UKJ1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PILRA	ENST00000198536.7	TSL:1 MANE Select	c.682C>T	p.Arg228Trp	missense	Exon 4 of 7	ENSP00000198536.2	Q9UKJ1-1
	PILRA	ENST00000350573.2	TSL:1	c.463C>T	p.Arg155Trp	missense	Exon 3 of 6	ENSP00000340109.2	Q9UKJ1-3
	PILRA	ENST00000453419.5	TSL:1	c.463C>T	p.Arg155Trp	missense	Exon 3 of 6	ENSP00000390026.1	C9JJ79

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251318 AF XY: 0.000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85 AN XY: 727122

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000201 AC: 9 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86234

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53420

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5672

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111906

Other (OTH) AF: 0.000133 AC: 8 AN: 60370

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152154 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68012

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.26
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.080
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.047	D
Polyphen		0.96	D
Vest4		0.31
MutPred		0.33		Loss of disorder (P = 0.0397)
MVP		0.67
MPC		0.35
ClinPred		0.95	D
GERP RS		-1.1
Varity_R		0.079
gMVP		0.14
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs145267648; hg19: chr7-99995510; COSMIC: COSV52200174; COSMIC: COSV52200174;