chr12-6816241-C-T

Position:

chr12-6816241-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a mutagenesis_site Has no effect on the interaction with MHCII. Impairs recognition by OKT4 antibody. (size 0) in uniprot entity CD4_HUMAN

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 id 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/exons	MANE	Protein	UniProt
CD4	NM_000616.5 linkuse as main transcript	c.793C>T	p.Arg265Trp	missense_variant	6/10	ENST00000011653.9	NP_000607.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD4	ENST00000011653.9 linkuse as main transcript	c.793C>T	p.Arg265Trp	missense_variant	6/10	1	NM_000616.5	ENSP00000011653	P1

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

GnomAD3 exomes

AF:

0.0191

AC:

4780

AN:

250838

Hom.:

358

AF XY:

0.0151

AC XY:

2050

AN XY:

135646

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 SAS exome

AF:

0.00467

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

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.0138

Gnomad4 ASJ exome

AF:

0.0163

Gnomad4 EAS exome

AF:

0.0477

Gnomad4 SAS exome

AF:

0.00444

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.0166

GnomAD4 genome

AF:

0.0597

AC:

9083

AN:

152238

Hom.:

834

Cov.:

AF XY:

0.0580

AC XY:

4318

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.198

Gnomad4 AMR

AF:

0.0280

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.0342

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0132

Hom.:

268

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

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1993	- -

not specified

Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2019

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

1.0

P;P

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

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

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