1-167433975-G-A

Variant names:

• chr1-167433975-G-A
• rs952963
• NM_198053.3:c.393+45C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198053.3(CD247):​c.393+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,530,668 control chromosomes in the GnomAD database, including 10,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1585 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9245 hom.)
• Consequence: CD247 NM_198053.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.940
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-167433975-G-A is Benign according to our data. Variant chr1-167433975-G-A is described in ClinVar as Benign. ClinVar VariationId is 1265565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD247	NM_198053.3	c.393+45C>T		intron_variant	Intron 6 of 7	ENST00000362089.10	NP_932170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD247	ENST00000362089.10	c.393+45C>T		intron_variant	Intron 6 of 7	1	NM_198053.3	ENSP00000354782.5

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20824 AN: 152118 Hom.: 1584 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0806

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.0902

Gnomad FIN AF: 0.0889

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.117 AC: 29467 AN: 251472 AF XY: 0.114

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.0964

Gnomad ASJ exome AF: 0.0787

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.0934

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.112 AC: 154022 AN: 1378432 Hom.: 9245 Cov.: 23 AF XY: 0.111 AC XY: 76914 AN XY: 690732

African (AFR) AF: 0.204 AC: 6505 AN: 31932

American (AMR) AF: 0.0977 AC: 4362 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 2057 AN: 25578

East Asian (EAS) AF: 0.231 AC: 9101 AN: 39332

South Asian (SAS) AF: 0.0864 AC: 7317 AN: 84664

European-Finnish (FIN) AF: 0.0946 AC: 5050 AN: 53368

Middle Eastern (MID) AF: 0.0983 AC: 551 AN: 5604

European-Non Finnish (NFE) AF: 0.109 AC: 112495 AN: 1035710

Other (OTH) AF: 0.114 AC: 6584 AN: 57600

GnomAD4 genome AF: 0.137 AC: 20835 AN: 152236 Hom.: 1585 Cov.: 33 AF XY: 0.135 AC XY: 10063 AN XY: 74438

African (AFR) AF: 0.196 AC: 8131 AN: 41516

American (AMR) AF: 0.110 AC: 1676 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 280 AN: 3472

East Asian (EAS) AF: 0.233 AC: 1206 AN: 5184

South Asian (SAS) AF: 0.0899 AC: 434 AN: 4828

European-Finnish (FIN) AF: 0.0889 AC: 943 AN: 10602

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7775 AN: 68022

Other (OTH) AF: 0.126 AC: 267 AN: 2114

Alfa AF: 0.110 Hom.: 602

Bravo AF: 0.140

Asia WGS AF: 0.175 AC: 607 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.51
PhyloP100		0.94
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: rs952963; hg19: chr1-167403212; COSMIC: COSV62979681;