rs2231441

Variant names:

• chr11-118304825-A-G
• rs2231441
• NM_000733.4:c.-60+49A>G

Variant summary

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

The NM_000733.4(CD3E):​c.-60+49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 819,292 control chromosomes in the GnomAD database, including 41,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6206 hom., cov: 33)
  • Exomes 𝑓: 0.32 (35059 hom.)
• Consequence: CD3E NM_000733.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.686
• Publications: 6 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.7).
• BP6: Variant 11-118304825-A-G is Benign according to our data. Variant chr11-118304825-A-G is described in ClinVar as Benign. ClinVar VariationId is 1178693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000733.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD3E	NM_000733.4	MANE Select	c.-60+49A>G		intron	N/A	NP_000724.1	P07766

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD3E	ENST00000361763.9	TSL:1 MANE Select	c.-60+49A>G		intron	N/A	ENSP00000354566.4	P07766
	CD3E	ENST00000853938.1		c.-128A>G		5_prime_UTR	Exon 1 of 8	ENSP00000523997.1
	CD3E	ENST00000526146.5	TSL:2	n.40+49A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39508 AN: 152078 Hom.: 6184 Cov.: 33

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.315 AC: 210245 AN: 667096 Hom.: 35059 Cov.: 8 AF XY: 0.315 AC XY: 113762 AN XY: 361150

African (AFR) AF: 0.0886 AC: 1617 AN: 18256

American (AMR) AF: 0.503 AC: 21887 AN: 43478

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 6277 AN: 20970

East Asian (EAS) AF: 0.205 AC: 7300 AN: 35574

South Asian (SAS) AF: 0.312 AC: 21838 AN: 69944

European-Finnish (FIN) AF: 0.328 AC: 16198 AN: 49424

Middle Eastern (MID) AF: 0.313 AC: 1089 AN: 3480

European-Non Finnish (NFE) AF: 0.316 AC: 123976 AN: 391966

Other (OTH) AF: 0.296 AC: 10063 AN: 34004

GnomAD4 genome AF: 0.260 AC: 39560 AN: 152196 Hom.: 6206 Cov.: 33 AF XY: 0.262 AC XY: 19485 AN XY: 74394

African (AFR) AF: 0.0906 AC: 3764 AN: 41556

American (AMR) AF: 0.398 AC: 6087 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1013 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1025 AN: 5182

South Asian (SAS) AF: 0.306 AC: 1479 AN: 4830

European-Finnish (FIN) AF: 0.333 AC: 3526 AN: 10574

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21626 AN: 67988

Other (OTH) AF: 0.295 AC: 623 AN: 2110

Alfa AF: 0.293 Hom.: 1470

Bravo AF: 0.259

Asia WGS AF: 0.240 AC: 838 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.39
DANN	Benign	0.82
PhyloP100		-0.69
PromoterAI		0.0053	Neutral
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: rs2231441; hg19: chr11-118175540; COSMIC: COSV62346624; COSMIC: COSV62346624;