14-21768357-C-A

Variant names:

• chr14-21768357-C-A
• rs766737

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 0.88 in 634,464 control chromosomes in the GnomAD database, including 247,371 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 0.88 (59132 hom., cov: 31)
  • Exomes 𝑓: 0.88 (188239 hom.)
• Consequence: TRA intragenic
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335

Genes affected

TRA (HGNC:12027):

TRAV6 (HGNC:12144): (T cell receptor alpha variable 6) 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRA		n.21768357C>A		intragenic_variant
TRAV6	unassigned_transcript_2187	c.-196C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAV6	ENST00000390428.3	c.-139C>A		upstream_gene_variant		6		ENSP00000438290.1

Frequencies

GnomAD3 genomes AF: 0.880 AC: 133754 AN: 152020 Hom.: 59128 Cov.: 31

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.990

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.921

Gnomad OTH AF: 0.894

GnomAD4 exome AF: 0.880 AC: 424590 AN: 482326 Hom.: 188239 AF XY: 0.880 AC XY: 226136 AN XY: 256836

Gnomad4 AFR exome AF: 0.876

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.941

Gnomad4 EAS exome AF: 0.691

Gnomad4 SAS exome AF: 0.845

Gnomad4 FIN exome AF: 0.785

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.882

GnomAD4 genome AF: 0.879 AC: 133804 AN: 152138 Hom.: 59132 Cov.: 31 AF XY: 0.870 AC XY: 64700 AN XY: 74368

Gnomad4 AFR AF: 0.882

Gnomad4 AMR AF: 0.823

Gnomad4 ASJ AF: 0.935

Gnomad4 EAS AF: 0.684

Gnomad4 SAS AF: 0.821

Gnomad4 FIN AF: 0.779

Gnomad4 NFE AF: 0.921

Gnomad4 OTH AF: 0.887

Alfa AF: 0.900 Hom.: 7646

Bravo AF: 0.883

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs766737; hg19: chr14-22236597;