rs141902449

chr11-118342556-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000732.6(CD3D):c.52C>A(p.Gln18Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,613,512 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: CD3D NM_000732.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.23

Genes affected

CD3D (HGNC:1673): (CD3 delta subunit of T-cell receptor complex) The protein encoded by this gene is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. The encoded membrane protein represents the delta subunit of the CD3 complex, and along with four other CD3 subunits, binds either TCR alpha/beta or TCR gamma/delta to form the TCR/CD3 complex on the surface of T-cells. Defects in this gene are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (SCIDBNK). Two transcript variants encoding different isoforms have been found for this gene. Other variants may also exist, but the full-length natures of their transcripts has yet to be defined. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018796057).
• BP6: Variant 11-118342556-G-T is Benign according to our data. Variant chr11-118342556-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 541671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118342556-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000795 (121/152216) while in subpopulation AFR AF= 0.00287 (119/41522). AF 95% confidence interval is 0.00245. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD3D	NM_000732.6	c.52C>A	p.Gln18Lys	missense_variant	1/5	ENST00000300692.9
CD3D	NM_001040651.2	c.52C>A	p.Gln18Lys	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD3D	ENST00000300692.9	c.52C>A	p.Gln18Lys	missense_variant	1/5	1	NM_000732.6	P1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152098 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251200 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135758

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461296 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 726994

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152216 Hom.: 1 Cov.: 31 AF XY: 0.000712 AC XY: 53 AN XY: 74440

Gnomad4 AFR AF: 0.00287

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000888

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 19 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 03, 2024	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.67	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.088	T;D;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.28	B;.;.
Vest4		0.34
MVP		0.82
MPC		0.41
ClinPred		0.044	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.75

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: rs141902449; hg19: chr11-118213271;