Genetic Variant NM_001282556.2:c.319T>A (chr3-108353681-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001282556.2(HHLA2):c.319T>A(p.Phe107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HHLA2
NM_001282556.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.180

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]

HHLA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1471622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHLA2	NM_001282556.2 link	c.319T>A	p.Phe107Ile	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
HHLA2	ENST00000467761.6 link	c.319T>A	p.Phe107Ile	missense_variant	Exon 4 of 10	5	NM_001282556.2	ENSP00000419207.1		Q9UM44-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461390

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111740

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.319T>A (p.F107I) alteration is located in exon 4 (coding exon 2) of the HHLA2 gene. This alteration results from a T to A substitution at nucleotide position 319, causing the phenylalanine (F) at amino acid position 107 to be replaced by an isoleucine (I). 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

0.061

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.8

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0027

T;T;.;T;.;T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.58

T;T;T;T;T;.;.;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.040

N;.;.;.;.;N;N;N

PhyloP100

0.18

PrimateAI

Benign

0.32

PROVEAN

Benign

0.47

.;N;N;N;N;N;N;N

REVEL

Benign

0.071

Sift

Benign

0.35

.;T;T;T;T;T;T;T

Sift4G

Benign

0.44

T;T;T;T;T;T;T;T

Polyphen

0.0030

B;.;.;B;.;B;B;B

Vest4

0.16

MutPred

0.45

Loss of phosphorylation at S112 (P = 0.2491);.;Loss of phosphorylation at S112 (P = 0.2491);Loss of phosphorylation at S112 (P = 0.2491);Loss of phosphorylation at S112 (P = 0.2491);Loss of phosphorylation at S112 (P = 0.2491);Loss of phosphorylation at S112 (P = 0.2491);Loss of phosphorylation at S112 (P = 0.2491);

MVP

0.43

MPC

0.24

ClinPred

0.16

GERP RS

-3.3

PromoterAI

-0.0094

Neutral

(source)

Varity_R

0.039

gMVP

0.39

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over