rs4435168

Variant names:

• chr14-22281859-T-C
• rs4435168

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The variant allele was found at a frequency of 0.102 in 710,752 control chromosomes in the GnomAD database, including 4,395 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 0.081 (648 hom., cov: 25)
  • Exomes 𝑓: 0.11 (3747 hom.)
• Consequence: TRA intragenic
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810
• Publications: 3 publications found

Genes affected

TRA (HGNC:12027):

TRD-AS1 (HGNC:56197): (TRD antisense RNA 1)

TRAV38-2DV8 (HGNC:12138): (T cell receptor alpha variable 38-2/delta variable 8) 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRA		n.22281859T>C		intragenic_variant
TRAV38-2DV8	unassigned_transcript_2232	c.*114T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRD-AS1	ENST00000656379.1	n.271-80477A>G		intron_variant	Intron 3 of 3
TRAV38-2DV8	ENST00000390465.2	c.*111T>C		downstream_gene_variant		6		ENSP00000452332.1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12221 AN: 150302 Hom.: 644 Cov.: 25

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0843

Gnomad EAS AF: 0.0751

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0979

GnomAD2 exomes AF: 0.116 AC: 18020 AN: 154860 AF XY: 0.119

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.0822

Gnomad FIN exome AF: 0.0841

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.108 AC: 60357 AN: 560332 Hom.: 3747 Cov.: 0 AF XY: 0.111 AC XY: 33892 AN XY: 304934

African (AFR) AF: 0.0224 AC: 352 AN: 15740

American (AMR) AF: 0.161 AC: 5498 AN: 34214

Ashkenazi Jewish (ASJ) AF: 0.0899 AC: 1783 AN: 19834

East Asian (EAS) AF: 0.0647 AC: 2184 AN: 33772

South Asian (SAS) AF: 0.170 AC: 10543 AN: 61978

European-Finnish (FIN) AF: 0.0913 AC: 3274 AN: 35864

Middle Eastern (MID) AF: 0.114 AC: 462 AN: 4036

European-Non Finnish (NFE) AF: 0.102 AC: 33053 AN: 323864

Other (OTH) AF: 0.103 AC: 3208 AN: 31030

GnomAD4 genome AF: 0.0814 AC: 12239 AN: 150420 Hom.: 648 Cov.: 25 AF XY: 0.0816 AC XY: 5992 AN XY: 73428

African (AFR) AF: 0.0205 AC: 838 AN: 40804

American (AMR) AF: 0.119 AC: 1782 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 292 AN: 3462

East Asian (EAS) AF: 0.0758 AC: 390 AN: 5142

South Asian (SAS) AF: 0.174 AC: 818 AN: 4714

European-Finnish (FIN) AF: 0.0852 AC: 881 AN: 10344

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6909 AN: 67658

Other (OTH) AF: 0.0988 AC: 207 AN: 2096

Alfa AF: 0.102 Hom.: 1465

Bravo AF: 0.0821

Asia WGS AF: 0.100 AC: 348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.81
PhyloP100		-0.081
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4435168; hg19: chr14-22749742;