3-108355193-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001282556.2(HHLA2):​c.497C>T​(p.Pro166Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HHLA2
NM_001282556.2 missense

Scores

4
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45
Variant links:
Genes affected
HHLA2 (HGNC:4905): (HHLA2 member of B7 family) This gene encodes a protein ligand found on the surface of monocytes. The encoded protein is thought to regulate cell-mediated immunity by binding to a receptor on T lymphocytes and inhibiting the proliferation of these cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HHLA2NM_001282556.2 linkc.497C>T p.Pro166Leu missense_variant Exon 5 of 10 ENST00000467761.6 NP_001269485.1 Q9UM44-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HHLA2ENST00000467761.6 linkc.497C>T p.Pro166Leu missense_variant Exon 5 of 10 5 NM_001282556.2 ENSP00000419207.1 Q9UM44-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461436
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726980
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 27, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.497C>T (p.P166L) alteration is located in exon 5 (coding exon 3) of the HHLA2 gene. This alteration results from a C to T substitution at nucleotide position 497, causing the proline (P) at amino acid position 166 to be replaced by a leucine (L). 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
Uncertain
0.45
BayesDel_addAF
Uncertain
0.020
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;T;.;T;T;T
Eigen
Benign
-0.087
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.27
N
LIST_S2
Benign
0.85
T;T;T;.;.;.
M_CAP
Benign
0.019
T
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.0
M;.;.;M;M;M
PrimateAI
Benign
0.43
T
PROVEAN
Pathogenic
-9.6
.;D;D;D;D;D
REVEL
Benign
0.20
Sift
Pathogenic
0.0
.;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
0.98
D;D;.;D;D;D
Vest4
0.62
MutPred
0.85
Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP
0.50
MPC
0.70
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.45
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs2081863518; hg19: chr3-108074040; COSMIC: COSV63317544; COSMIC: COSV63317544; API