rs28919570

Positions:

• chr12-6816241-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -2.02

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]

ACMG classification

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	UniProt
CD4	NM_000616.5	c.793C>T	p.Arg265Trp	missense_variant	6/10	ENST00000011653.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9064 AN: 152120 Hom.: 831 Cov.: 32

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

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.: 34 AF XY: 0.00779 AC XY: 5664 AN XY: 727242

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.: 32 AF XY: 0.0580 AC XY: 4318 AN XY: 74442

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: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.201 AC: 887

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.0220 AC: 2672

Asia WGS AF: 0.0280 AC: 99 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Okt4 epitope deficiency Pathogenic:1 Benign: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, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.46
DANN	Benign	0.69
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.036
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0010	B
Vest4		0.070
MPC		0.21
ClinPred		0.044	T
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

Other links and lift over

dbSNP: rs28919570; hg19: chr12-6925407; COSMIC: COSV50590741; COSMIC: COSV50590741;