rs143949187

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000733.4(CD3E):c.103C>T(p.Pro35Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,611,270 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P35P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 13 hom. )

Consequence

CD3E
NM_000733.4 missense, splice_region

Scores

Splicing: ADA: 0.0002600

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.08

Publications

5 publications found

Variant links:

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]

CD3E Gene-Disease associations (from GenCC):

immunodeficiency 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CD3E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0059017837).

BP6

Variant 11-118312170-C-T is Benign according to our data. Variant chr11-118312170-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (423/152216) while in subpopulation NFE AF = 0.00369 (251/68024). AF 95% confidence interval is 0.00331. There are 6 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD3E	NM_000733.4 link	c.103C>T	p.Pro35Ser	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000361763.9	NP_000724.1	P07766

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD3E	ENST00000361763.9 link	c.103C>T	p.Pro35Ser	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_000733.4	ENSP00000354566.4		P07766

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

423

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00274

AC:

690

AN:

251422

AF XY:

0.00275

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00191

AC:

2783

AN:

1459054

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1455

AN XY:

726042

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33422

American (AMR)

AF:

0.000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26110

East Asian (EAS)

AF:

0.000126

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.0136

AC:

726

AN:

53396

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00168

AC:

1864

AN:

1109476

Other (OTH)

AF:

0.00144

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

140

280

421

561

701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00278

AC:

423

AN:

152216

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41534

American (AMR)

AF:

0.000392

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0140

AC:

148

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00369

AC:

251

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00247

Hom.:

Bravo

AF:

0.00130

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00244

AC:

296

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 18

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CD3E: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.012

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.21

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.30

M_CAP

Benign

0.029

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

-3.1

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

REVEL

Benign

0.043

Sift

Benign

0.48

Sift4G

Benign

0.73

Polyphen

0.042

Vest4

0.089

MVP

0.29

MPC

0.10

ClinPred

0.0088

GERP RS

-2.3

Varity_R

0.15

gMVP

0.54

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over