7-100397887-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PILRA
NM_013439.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.257
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10436025).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PILRANM_013439.3 linkc.682C>T p.Arg228Trp missense_variant Exon 4 of 7 ENST00000198536.7 NP_038467.2 Q9UKJ1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PILRAENST00000198536.7 linkc.682C>T p.Arg228Trp missense_variant Exon 4 of 7 1 NM_013439.3 ENSP00000198536.2 Q9UKJ1-1
ENSG00000289690ENST00000695708 linkc.-1315C>T 5_prime_UTR_variant Exon 1 of 10 ENSP00000512108.1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152154
Hom.:
0
Cov.:
31
show subpopulations
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
GnomAD3 exomes
AF:
0.000167
AC:
42
AN:
251318
Hom.:
0
AF XY:
0.000169
AC XY:
23
AN XY:
135828
show subpopulations
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 SAS exome
AF:
0.000359
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000348
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.0000800
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152154
Hom.:
0
Cov.:
31
AF XY:
0.0000942
AC XY:
7
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000478
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

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 09, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.682C>T (p.R228W) alteration is located in exon 4 (coding exon 4) of the PILRA gene. This alteration results from a C to T substitution at nucleotide position 682, causing the arginine (R) at amino acid position 228 to be replaced by a tryptophan (W). 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
0.093
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
17
DANN
Benign
0.89
DEOGEN2
Benign
0.020
.;T;T;.
Eigen
Benign
-0.89
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.053
N
LIST_S2
Benign
0.49
T;T;T;T
M_CAP
Benign
0.0075
T
MetaRNN
Benign
0.10
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
.;N;.;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.5
N;N;N;N
REVEL
Benign
0.080
Sift
Uncertain
0.012
D;D;D;D
Sift4G
Uncertain
0.047
D;D;D;D
Polyphen
0.96, 1.0, 0.95
.;D;D;P
Vest4
0.31, 0.30, 0.34
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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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