chr3-108353477-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001282556.2(HHLA2):​c.115G>A​(p.Val39Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,602,986 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

HHLA2
NM_001282556.2 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.584

Publications

0 publications found
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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03918621).
BP6
Variant 3-108353477-G-A is Benign according to our data. Variant chr3-108353477-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2344527.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HHLA2NM_001282556.2 linkc.115G>A p.Val39Ile missense_variant Exon 4 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.115G>A p.Val39Ile missense_variant Exon 4 of 10 5 NM_001282556.2 ENSP00000419207.1 Q9UM44-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152104
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000120
AC:
28
AN:
232934
AF XY:
0.0000793
show subpopulations
Gnomad AFR exome
AF:
0.0000703
Gnomad AMR exome
AF:
0.000771
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000192
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000358
AC:
52
AN:
1450882
Hom.:
0
Cov.:
34
AF XY:
0.0000291
AC XY:
21
AN XY:
720696
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33364
American (AMR)
AF:
0.000653
AC:
28
AN:
42890
Ashkenazi Jewish (ASJ)
AF:
0.0000387
AC:
1
AN:
25818
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39392
South Asian (SAS)
AF:
0.0000354
AC:
3
AN:
84644
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52770
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
0.0000181
AC:
20
AN:
1106202
Other (OTH)
AF:
0.00
AC:
0
AN:
60054
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152104
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74298
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41424
American (AMR)
AF:
0.000197
AC:
3
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.535
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.0000982
ExAC
AF:
0.0000829
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Aug 10, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
0.85
DANN
Benign
0.72
DEOGEN2
Benign
0.013
T;T;.;T;.;T;T;T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.55
T;T;T;T;T;T;.;.;.
M_CAP
Benign
0.0080
T
MetaRNN
Benign
0.039
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.;.;.;.;.;L;L;L
PhyloP100
0.58
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.44
.;N;N;N;N;N;N;N;N
REVEL
Benign
0.071
Sift
Benign
0.13
.;T;T;T;T;T;T;T;T
Sift4G
Benign
0.41
T;T;T;T;T;T;T;T;T
Polyphen
0.031
B;.;.;B;.;.;B;B;B
Vest4
0.093
MutPred
0.52
Loss of catalytic residue at V39 (P = 0.0824);.;Loss of catalytic residue at V39 (P = 0.0824);Loss of catalytic residue at V39 (P = 0.0824);Loss of catalytic residue at V39 (P = 0.0824);Loss of catalytic residue at V39 (P = 0.0824);Loss of catalytic residue at V39 (P = 0.0824);Loss of catalytic residue at V39 (P = 0.0824);Loss of catalytic residue at V39 (P = 0.0824);
MVP
0.12
MPC
0.18
ClinPred
0.029
T
GERP RS
0.18
PromoterAI
-0.0097
Neutral
Varity_R
0.029
gMVP
0.11
Mutation Taster
=97/3
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs770873611; hg19: chr3-108072324; COSMIC: COSV100755537; COSMIC: COSV100755537; API