6-42923316-C-G

Variant names:

• chr6-42923316-C-G
• rs200182239
• NM_138296.3:c.348C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138296.3(PTCRA):​c.348C>G​(p.His116Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: PTCRA NM_138296.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.39

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0058499873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCRA	NM_138296.3	c.348C>G	p.His116Gln	missense_variant	Exon 2 of 4	ENST00000304672.6	NP_612153.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCRA	ENST00000304672.6	c.348C>G	p.His116Gln	missense_variant	Exon 2 of 4	1	NM_138296.3	ENSP00000304447.2
PTCRA	ENST00000441198.4	c.273C>G	p.His91Gln	missense_variant	Exon 3 of 5	1		ENSP00000409550.1
PTCRA	ENST00000446507.5	c.59-913C>G		intron_variant	Intron 1 of 2	1		ENSP00000392288.1
PTCRA	ENST00000616441.2	c.348C>G	p.His116Gln	missense_variant	Exon 2 of 4	2		ENSP00000477815.1

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 22 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 250790 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461828 Hom.: 0 Cov.: 33 AF XY: 0.0000839 AC XY: 61 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74390

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.348C>G (p.H116Q) alteration is located in exon 2 (coding exon 2) of the PTCRA gene. This alteration results from a C to G substitution at nucleotide position 348, causing the histidine (H) at amino acid position 116 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.1
DANN	Benign	0.83
DEOGEN2	Benign	0.085	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.65	N;N;.
REVEL	Benign	0.056
Sift	Benign	0.55	T;T;.
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.017
MutPred		0.064		Loss of catalytic residue at H116 (P = 0.057);.;Loss of catalytic residue at H116 (P = 0.057);
MVP		0.11
MPC		0.14
ClinPred		0.025	T
GERP RS		-8.0
Varity_R		0.18
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200182239; hg19: chr6-42891054;