chr11-118304969-A-C

Variant names:

• chr11-118304969-A-C
• rs1009249314
• NM_000733.4:c.17A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000733.4(CD3E):​c.17A>C​(p.His6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD3E NM_000733.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12520021).

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.17A>C	p.His6Pro	missense	Exon 2 of 9	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.17A>C	p.His6Pro	missense	Exon 2 of 9	ENSP00000354566.4	P07766
	CD3E	ENST00000853938.1		c.17A>C	p.His6Pro	missense	Exon 1 of 8	ENSP00000523997.1
	CD3E	ENST00000528600.1	TSL:5	c.17A>C	p.His6Pro	missense	Exon 1 of 7	ENSP00000433975.1	E9PSH8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.67
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.24
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.027
Sift	Benign	0.21	T
Sift4G	Uncertain	0.040	D
Polyphen		0.022	B
Vest4		0.081
MutPred		0.40		Loss of MoRF binding (P = 0.0329)
MVP		0.28
MPC		0.16
ClinPred		0.026	T
GERP RS		0.33
PromoterAI		-0.013	Neutral
Varity_R		0.088
gMVP		0.73
Mutation Taster		=90/10	polymorphism

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: rs1009249314; hg19: chr11-118175684;