NM_138296.3:c.461G>T

Variant names:

• chr6-42925297-G-T
• rs745333497
• NM_138296.3:c.461G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138296.3(PTCRA):​c.461G>T​(p.Arg154Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,848 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTCRA NM_138296.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• Publications: 3 publications found

Genes affected

PTCRA (HGNC:21290): (pre T cell antigen receptor alpha) The protein encoded by this gene is a single-pass type I membrane protein that is found in immmature but not mature T-cells. Along with TCRB and CD3 complex, the encoded protein forms the pre-T-cell receptor complex, which regulates early T-cell development. Four transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

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_138296.3. 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
	PTCRA	NM_138296.3	MANE Select	c.461G>T	p.Arg154Leu	missense	Exon 4 of 4	NP_612153.2	Q6ISU1-1
	PTCRA	NM_001243168.2		c.506G>T	p.Arg169Leu	missense	Exon 4 of 4	NP_001230097.1	A0A087WTE9
	PTCRA	NM_001243169.2		c.386G>T	p.Arg129Leu	missense	Exon 5 of 5	NP_001230098.1	Q6ISU1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCRA	ENST00000304672.6	TSL:1 MANE Select	c.461G>T	p.Arg154Leu	missense	Exon 4 of 4	ENSP00000304447.2	Q6ISU1-1
	PTCRA	ENST00000441198.4	TSL:1	c.386G>T	p.Arg129Leu	missense	Exon 5 of 5	ENSP00000409550.1	Q6ISU1-3
	PTCRA	ENST00000446507.5	TSL:1	c.140G>T	p.Arg47Leu	missense	Exon 3 of 3	ENSP00000392288.1	Q6ISU1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000143 AC: 3 AN: 209818 AF XY: 0.00000862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436848 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 43102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.00 AC: 0 AN: 84278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106798

Other (OTH) AF: 0.00 AC: 0 AN: 59688

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.32
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.45		Gain of ubiquitination at K159 (P = 0.0773)
MVP		0.80
MPC		0.69
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.37
gMVP		0.73
Mutation Taster		=38/62	disease causing

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: rs745333497; hg19: chr6-42893035;