Genetic Variant NM_001282556.2:c.78G>T (chr3-108353440-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001282556.2(HHLA2):c.78G>T(p.Leu26Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,573,904 control chromosomes in the GnomAD database, including 5 homozygotes. 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: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

HHLA2
NM_001282556.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.140

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007530272).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHLA2	NM_001282556.2 link	c.78G>T	p.Leu26Phe	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.78G>T	p.Leu26Phe	missense_variant	Exon 4 of 10	5	NM_001282556.2	ENSP00000419207.1		Q9UM44-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00104

AC:

207

AN:

198504

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.000329

Gnomad AMR exome

AF:

0.000948

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000110

Gnomad NFE exome

AF:

0.00197

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00202

AC:

2875

AN:

1421736

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1418

AN XY:

704064

show subpopulations

African (AFR)

AF:

0.000426

AC:

AN:

32836

American (AMR)

AF:

0.000871

AC:

AN:

39024

Ashkenazi Jewish (ASJ)

AF:

0.0000394

AC:

AN:

25372

East Asian (EAS)

AF:

0.00

AC:

AN:

38490

South Asian (SAS)

AF:

0.00

AC:

AN:

81812

European-Finnish (FIN)

AF:

0.000179

AC:

AN:

50214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00248

AC:

2706

AN:

1089250

Other (OTH)

AF:

0.00188

AC:

111

AN:

59038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152168

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41526

American (AMR)

AF:

0.00164

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00232

AC:

158

AN:

67996

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000535

AC:

ESP6500EA

AF:

0.00171

AC:

ExAC

AF:

0.000784

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.78G>T (p.L26F) alteration is located in exon 4 (coding exon 2) of the HHLA2 gene. This alteration results from a G to T substitution at nucleotide position 78, causing the leucine (L) at amino acid position 26 to be replaced by a phenylalanine (F). 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

0.068

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.87

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.0074

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.49

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

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0075

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;.;.;.;L;L;L

PhyloP100

-0.14

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.49

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

REVEL

Benign

0.095

Sift

Benign

0.18

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

Sift4G

Benign

0.79

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

Polyphen

0.61

P;.;P;.;.;P;P;P

Vest4

0.067

MutPred

0.52

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

0.099

MPC

0.18

ClinPred

0.016

GERP RS

-1.1

PromoterAI

0.0098

Neutral

(source)

Varity_R

0.040

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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NM_001282556.2:c.78G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over