dbSNP rs529096683: HHLA2:p.Pro50Ser (chr3-108353510-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001282556.2(HHLA2):c.148C>T(p.Pro50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HHLA2
NM_001282556.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHLA2	NM_001282556.2 link	c.148C>T	p.Pro50Ser	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.148C>T	p.Pro50Ser	missense_variant	Exon 4 of 10	5	NM_001282556.2	ENSP00000419207.1		Q9UM44-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244652

Hom.:

AF XY:

0.00000754

AC XY:

AN XY:

132662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000569

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458886

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148C>T (p.P50S) alteration is located in exon 4 (coding exon 2) of the HHLA2 gene. This alteration results from a C to T substitution at nucleotide position 148, causing the proline (P) at amino acid position 50 to be replaced by a serine (S). 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

0.33

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

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

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;M;M;M

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

.;N;N;N;D;D;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.15

.;T;T;T;T;D;T;T;T

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;D;.;.;D;D;D

Vest4

0.67

MutPred

0.66

Gain of disorder (P = 0.0573);.;Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);

MVP

0.89

MPC

0.69

ClinPred

0.90

GERP RS

4.5

Varity_R

0.050

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over