14-22493922-G-C

Variant names:

• chr14-22493922-G-C
• rs10483278

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The variant allele was found at a frequency of 0.017 in 739,408 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (71 hom., cov: 28)
  • Exomes 𝑓: 0.015 (149 hom.)
• Consequence: TRA intragenic
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53

Genes affected

TRA (HGNC:12027):

TRAJ45 (HGNC:12076): (T cell receptor alpha joining 45) T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. This region represents the germline organization of the T cell receptor alpha and delta loci. Both the alpha and delta loci include V (variable), J (joining), and C (constant) segments and the delta locus also includes diversity (D) segments. The delta locus is situated within the alpha locus, between the alpha V and J segments. During T cell development, the delta chain is synthesized by a recombination event at the DNA level joining a D segment with a J segment; a V segment is then joined to the D-J gene. The alpha chain is synthesized by recombination joining a single V segment with a J segment. For both chains, the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase. Five variable segments can be used in either alpha or delta chains and are described by TRAV/DV symbols. Several V and J segments of the alpha locus are known to be incapable of encoding a protein and are considered pseudogenes. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRA		n.22493922G>C		intragenic_variant
TRAJ45	unassigned_transcript_2262	c.-5G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAJ45	ENST00000390492.1	c.-5G>C		upstream_gene_variant		6		ENSP00000451312.1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3489 AN: 149408 Hom.: 71 Cov.: 28

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00263

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.00502

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0161 AC: 3384 AN: 210128 Hom.: 56 AF XY: 0.0167 AC XY: 1912 AN XY: 114192

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00371

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0323

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0154 AC: 9091 AN: 589882 Hom.: 149 Cov.: 0 AF XY: 0.0163 AC XY: 5248 AN XY: 322108

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.00284

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0322

Gnomad4 FIN exome AF: 0.00781

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0176

GnomAD4 genome AF: 0.0233 AC: 3490 AN: 149526 Hom.: 71 Cov.: 28 AF XY: 0.0230 AC XY: 1680 AN XY: 73114

Gnomad4 AFR AF: 0.0521

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00263

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.00502

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0173 Hom.: 10

Bravo AF: 0.0254

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.53

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10483278; hg19: chr14-22962908;