11-118305004-G-A

Position:

chr11-118305004-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1

The NM_000733.4(CD3E):c.49+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,613,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

CD3E
NM_000733.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.00006318

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.321

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-118305004-G-A is Benign according to our data. Variant chr11-118305004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541658.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}. Variant chr11-118305004-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0004 (61/152358) while in subpopulation NFE AF= 0.000676 (46/68038). AF 95% confidence interval is 0.00052. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD3E	NM_000733.4 linkuse as main transcript	c.49+3G>A		splice_donor_region_variant, intron_variant		ENST00000361763.9	NP_000724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD3E	ENST00000361763.9 linkuse as main transcript	c.49+3G>A		splice_donor_region_variant, intron_variant		1	NM_000733.4	ENSP00000354566	P1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000438

AC:

110

AN:

251176

Hom.:

AF XY:

0.000420

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000802

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000616

AC:

900

AN:

1461228

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

463

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000731

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000400

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000577

Hom.:

Bravo

AF:

0.000453

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency 18

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change falls in intron 2 of the CD3E gene. It does not directly change the encoded amino acid sequence of the CD3E protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs202200315, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CD3E-related conditions. ClinVar contains an entry for this variant (Variation ID: 541658). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000063

dbscSNV1_RF

Benign

0.016

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