chr1-167435434-G-A

Position:

chr1-167435434-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_198053.3(CD247):c.301C>T(p.Gln101*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,611,206 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

CD247
NM_198053.3 stop_gained, splice_region

Scores

Splicing: ADA: 0.8434

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.50

Variant links:

Genes affected

CD247 (HGNC:1677): (CD247 molecule) The protein encoded by this gene is T-cell receptor zeta, which together with T-cell receptor alpha/beta and gamma/delta heterodimers, and with CD3-gamma, -delta and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CD247 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-167435434-G-A is Pathogenic according to our data. Variant chr1-167435434-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-167435434-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD247	NM_198053.3 link	c.301C>T	p.Gln101*	stop_gained, splice_region_variant	5/8	ENST00000362089.10	NP_932170.1	P20963-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD247	ENST00000362089.10 link	c.301C>T	p.Gln101*	stop_gained, splice_region_variant	5/8	1	NM_198053.3	ENSP00000354782.5		P20963-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000263

AC:

AN:

250742

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.000353

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000280

AC:

408

AN:

1459022

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

210

AN XY:

726076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000936

Gnomad4 NFE exome

AF:

0.000295

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000204

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000227

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 25

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change creates a premature translational stop signal (p.Gln101*) in the CD247 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD247 are known to be pathogenic (PMID: 17170122, 26542031). This variant is present in population databases (rs55729925, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CD247-related conditions. ClinVar contains an entry for this variant (Variation ID: 419227). For these reasons, this variant has been classified as Pathogenic. -

CD247-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

The CD247 c.301C>T variant is predicted to result in premature protein termination (p.Gln101*). This variant was reported in the heterozygous state, and interpreted as pathogenic, in individuals undergoing preconception carrier screening analyses (Supplementary Table 001, Capalbo et al. 2019. PubMed ID: 31589614). This variant is reported in 0.068% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in CD247 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 30, 2024

Variant summary: CD247 c.301C>T (p.Gln101X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00026 in 250742 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CD247 causing Severe Combined Immunodeficiency (0.00026 vs 0.00035), allowing no conclusion about variant significance. c.301C>T has been reported in the literature in individuals affected with Primary immunodeficiencies (examples: Gallo_2016 and Rudilla_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27872624, 31681265). ClinVar contains an entry for this variant (Variation ID: 419227). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2015

The Q101X nonsense variant in the CD3Z gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q101X variant was not observed at any significant frequency in approximately 8,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

Vest4

0.66

GERP RS

4.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Pathogenic

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over