NM_000616.5:c.793C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000616.5(CD4):c.793C>T(p.Arg265Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,120 control chromosomes in the GnomAD database, including 1,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 834 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 777 hom. )

Consequence

CD4
NM_000616.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: -2.02

Publications

27 publications found

Variant links:

Genes affected

CD4 (HGNC:1678): (CD4 molecule) This gene encodes the CD4 membrane glycoprotein of T lymphocytes. The CD4 antigen acts as a coreceptor with the T-cell receptor on the T lymphocyte to recognize antigens displayed by an antigen presenting cell in the context of class II MHC molecules. The CD4 antigen is also a primary receptor for entry of the human immunodeficiency virus through interactions with the HIV Env gp120 subunit. This gene is expressed not only in T lymphocytes, but also in B cells, macrophages, granulocytes, as well as in various regions of the brain. The protein functions to initiate or augment the early phase of T-cell activation, and may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been identified in this gene. [provided by RefSeq, May 2020]

CD4 Gene-Disease associations (from GenCC):

immunodeficiency 79
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CD4 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=0.0041941702).

BP6

Variant 12-6816241-C-T is Benign according to our data. Variant chr12-6816241-C-T is described in ClinVar as Benign. ClinVar VariationId is 29898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD4	NM_000616.5 link	c.793C>T	p.Arg265Trp	missense_variant	Exon 6 of 10	ENST00000011653.9	NP_000607.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD4	ENST00000011653.9 link	c.793C>T	p.Arg265Trp	missense_variant	Exon 6 of 10	1	NM_000616.5	ENSP00000011653.4

Frequencies

GnomAD3 genomes

AF:

0.0596

AC:

9064

AN:

152120

Hom.:

831

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0281

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.0345

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0191

AC:

4780

AN:

250838

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.204

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.0291

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00851

AC:

12438

AN:

1461882

Hom.:

777

Cov.:

AF XY:

0.00779

AC XY:

5664

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.201

AC:

6745

AN:

33480

American (AMR)

AF:

0.0138

AC:

617

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

427

AN:

26136

East Asian (EAS)

AF:

0.0477

AC:

1892

AN:

39698

South Asian (SAS)

AF:

0.00444

AC:

383

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00116

AC:

1293

AN:

1112006

Other (OTH)

AF:

0.0166

AC:

1004

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

673

1346

2018

2691

3364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.0597

AC:

9083

AN:

152238

Hom.:

834

Cov.:

AF XY:

0.0580

AC XY:

4318

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.198

AC:

8208

AN:

41492

American (AMR)

AF:

0.0280

AC:

428

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3472

East Asian (EAS)

AF:

0.0342

AC:

177

AN:

5182

South Asian (SAS)

AF:

0.00704

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68022

Other (OTH)

AF:

0.0430

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

372

744

1117

1489

1861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0243

Hom.:

792

Bravo

AF:

0.0689

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.201

AC:

887

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.0220

AC:

2672

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00154

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Okt4 epitope deficiency

Pathogenic:1Benign:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

NM_000616.4:c.793C>T (p.Arg265Trp) in the gene CD4 was reported as c.867G>A (p.Arg240Trp). Hodge et al reported this variant in a OKT4-Epitope deficiency patient (PMID: 1708753). In addition, Takenaka et al. reported homozygosity of this variant in patients with OKT4 epitope deficiency (PMID: 7689618). It has an allele frequency of 0.201 in African subpopulation in the gnomAD database. 516 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1; BS2; PM3_Supporting; PP4. -

Sep 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.188, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

CD4-related disorder

Benign:1

Dec 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.46

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.22

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

PhyloP100

-2.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-2.3

REVEL

Benign

0.036

Sift

Uncertain

0.010

Sift4G

Uncertain

0.032

Polyphen

0.0010

Vest4

0.070

MPC

0.21

ClinPred

0.044

GERP RS

-9.2

Varity_R

0.17

gMVP

0.47

Mutation Taster

=91/9

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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