rs2231449

Variant names:

• chr11-118315590-C-A
• rs2231449
• NM_000733.4:c.*48C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000733.4(CD3E):​c.*48C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,438,796 control chromosomes in the GnomAD database, including 588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (57 hom., cov: 30)
  • Exomes 𝑓: 0.026 (531 hom.)
• Consequence: CD3E NM_000733.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0990

Genes affected

CD3E (HGNC:1674): (CD3 epsilon subunit of T-cell receptor complex) The protein encoded by this gene is the CD3-epsilon polypeptide, which together with CD3-gamma, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The genes encoding the epsilon, gamma and delta polypeptides are located in the same cluster on chromosome 11. The epsilon polypeptide plays an essential role in T-cell development. Defects in this gene cause immunodeficiency. This gene has also been linked to a susceptibility to type I diabetes in women. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-118315590-C-A is Benign according to our data. Variant chr11-118315590-C-A is described in ClinVar as [Benign]. Clinvar id is 302665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118315590-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD3E	NM_000733.4	c.*48C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000361763.9	NP_000724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD3E	ENST00000361763.9	c.*48C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000733.4	ENSP00000354566.4
CD3E	ENST00000528600.1	c.*48C>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000433975.1
CD3E	ENST00000526146.5	n.2058C>A		non_coding_transcript_exon_variant	Exon 7 of 7	2
CD3E	ENST00000531913.1	n.1043C>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3387 AN: 152020 Hom.: 58 Cov.: 30

Gnomad AFR AF: 0.00585

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.0445

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0292 AC: 5404 AN: 185118 Hom.: 124 AF XY: 0.0273 AC XY: 2679 AN XY: 98286

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.0633

Gnomad ASJ exome AF: 0.00475

Gnomad EAS exome AF: 0.0492

Gnomad SAS exome AF: 0.00622

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0264 AC: 34015 AN: 1286658 Hom.: 531 Cov.: 20 AF XY: 0.0253 AC XY: 16288 AN XY: 642786

Gnomad4 AFR exome AF: 0.00430

Gnomad4 AMR exome AF: 0.0599

Gnomad4 ASJ exome AF: 0.00535

Gnomad4 EAS exome AF: 0.0468

Gnomad4 SAS exome AF: 0.00562

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0222 AC: 3381 AN: 152138 Hom.: 57 Cov.: 30 AF XY: 0.0226 AC XY: 1680 AN XY: 74360

Gnomad4 AFR AF: 0.00583

Gnomad4 AMR AF: 0.0579

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.0444

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0262

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0233 Hom.: 25

Bravo AF: 0.0239

Asia WGS AF: 0.0250 AC: 85 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

- -

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency 18 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2231449; hg19: chr11-118186305;