chr3-108353510-C-T

Variant names:

• chr3-108353510-C-T
• rs529096683
• NM_001282556.2:c.148C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHLA2	NM_001282556.2	MANE Select	c.148C>T	p.Pro50Ser	missense	Exon 4 of 10	NP_001269485.1	Q9UM44-1
	HHLA2	NM_001282557.2		c.148C>T	p.Pro50Ser	missense	Exon 4 of 10	NP_001269486.1	Q9UM44-1
	HHLA2	NM_001370244.1		c.148C>T	p.Pro50Ser	missense	Exon 4 of 10	NP_001357173.1	Q9UM44-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHLA2	ENST00000467761.6	TSL:5 MANE Select	c.148C>T	p.Pro50Ser	missense	Exon 4 of 10	ENSP00000419207.1	Q9UM44-1
	HHLA2	ENST00000357759.9	TSL:1	c.148C>T	p.Pro50Ser	missense	Exon 4 of 10	ENSP00000350402.5	Q9UM44-1
	HHLA2	ENST00000489514.6	TSL:1	c.148C>T	p.Pro50Ser	missense	Exon 4 of 10	ENSP00000417856.2	Q9UM44-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244652 AF XY: 0.00000754

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458886 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725490

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110542

Other (OTH) AF: 0.0000166 AC: 1 AN: 60286

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.37
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.66		Gain of disorder (P = 0.0573)
MVP		0.89
MPC		0.69
ClinPred		0.90	D
GERP RS		4.5
PromoterAI		0.013	Neutral
Varity_R		0.050
gMVP		0.36
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs529096683; hg19: chr3-108072357;