3-108353747-G-C

Variant names:

• chr3-108353747-G-C
• NM_001282556.2:c.385G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001282556.2(HHLA2):​c.385G>C​(p.Val129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HHLA2 NM_001282556.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.104
• Publications: 0 publications found

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]

ACMG classification

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=0.091851026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHLA2	NM_001282556.2	c.385G>C	p.Val129Leu	missense_variant	Exon 4 of 10	ENST00000467761.6	NP_001269485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHLA2	ENST00000467761.6	c.385G>C	p.Val129Leu	missense_variant	Exon 4 of 10	5	NM_001282556.2	ENSP00000419207.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385G>C (p.V129L) alteration is located in exon 4 (coding exon 2) of the HHLA2 gene. This alteration results from a G to C substitution at nucleotide position 385, causing the valine (V) at amino acid position 129 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	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.27
DANN	Benign	0.77
DEOGEN2	Benign	0.0036	T;T;.;T;.;.;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.62	T;T;T;T;T;T;.;.;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.092	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.;N;N;N
PhyloP100		0.10
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.43	.;N;N;N;N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.48	.;T;T;T;T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;.;.;B;.;.;B;B;B
Vest4		0.034
MutPred		0.55		Loss of ubiquitination at K133 (P = 0.0755);.;Loss of ubiquitination at K133 (P = 0.0755);Loss of ubiquitination at K133 (P = 0.0755);.;Loss of ubiquitination at K133 (P = 0.0755);Loss of ubiquitination at K133 (P = 0.0755);Loss of ubiquitination at K133 (P = 0.0755);Loss of ubiquitination at K133 (P = 0.0755);
MVP		0.48
MPC		0.17
ClinPred		0.064	T
GERP RS		-8.2
PromoterAI		-0.0021	Neutral
Varity_R		0.030
gMVP		0.25
Mutation Taster		=98/2	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

hg19: chr3-108072594;