chr14-22464064-C-T

Variant names:

• chr14-22464064-C-T
• rs10483275
• ENST00000390477.2:c.344-140C>T

Variant summary

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

The ENST00000390477.2(TRDC):​c.344-140C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 629,574 control chromosomes in the GnomAD database, including 1,924 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 0.093 (792 hom., cov: 26)
  • Exomes 𝑓: 0.064 (1132 hom.)
• Consequence: TRDC ENST00000390477.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495
• Publications: 2 publications found

Genes affected

TRDC (HGNC:12253): (T cell receptor delta constant) 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]

TRA (HGNC:12027):

TRD (HGNC:12252):

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRA		n.22464064C>T		intragenic_variant
TRD		n.22464064C>T		intragenic_variant
TRDC	unassigned_transcript_2244	c.344-140C>T		intron_variant	Intron 2 of 3
TRD-AS1	NR_148361.1	n.225+17177G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDC	ENST00000390477.2	c.344-140C>T		intron_variant	Intron 2 of 3	6		ENSP00000451468.1
TRD-AS1	ENST00000514473.2	n.225+17177G>A		intron_variant	Intron 2 of 2	2
TRD-AS1	ENST00000556777.2	n.606-829G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 13965 AN: 150950 Hom.: 789 Cov.: 26

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0518

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.0965

GnomAD4 exome AF: 0.0644 AC: 30827 AN: 478506 Hom.: 1132 AF XY: 0.0620 AC XY: 15829 AN XY: 255124

African (AFR) AF: 0.163 AC: 2142 AN: 13180

American (AMR) AF: 0.0551 AC: 1298 AN: 23576

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 769 AN: 15268

East Asian (EAS) AF: 0.000253 AC: 8 AN: 31570

South Asian (SAS) AF: 0.0299 AC: 1483 AN: 49642

European-Finnish (FIN) AF: 0.0579 AC: 1819 AN: 31442

Middle Eastern (MID) AF: 0.0477 AC: 119 AN: 2496

European-Non Finnish (NFE) AF: 0.0747 AC: 21220 AN: 284006

Other (OTH) AF: 0.0721 AC: 1969 AN: 27326

GnomAD4 genome AF: 0.0925 AC: 13979 AN: 151068 Hom.: 792 Cov.: 26 AF XY: 0.0911 AC XY: 6721 AN XY: 73782

African (AFR) AF: 0.160 AC: 6552 AN: 40958

American (AMR) AF: 0.0787 AC: 1187 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0255 AC: 122 AN: 4786

European-Finnish (FIN) AF: 0.0619 AC: 646 AN: 10434

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0744 AC: 5045 AN: 67844

Other (OTH) AF: 0.0960 AC: 202 AN: 2104

Alfa AF: 0.0768 Hom.: 265

Bravo AF: 0.0981

Asia WGS AF: 0.0240 AC: 86 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.0
DANN	Benign	0.81
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10483275; hg19: chr14-22933056;