chr12-6816241-C-T

Variant names:

• chr12-6816241-C-T
• rs28919570
• NM_000616.5:c.793C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001195015.3(CD4):​c.-27C>T variant causes a 5 prime UTR premature start codon gain 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. 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_001195015.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: -2.02
• Publications: 27 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195015.3. 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
	CD4	NM_000616.5	MANE Select	c.793C>T	p.Arg265Trp	missense	Exon 6 of 10	NP_000607.1	P01730
	CD4	NM_001195015.3		c.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 8	NP_001181944.1	B4DT49
	CD4	NM_001195016.3		c.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 8	NP_001181945.1	B4DT49

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	ENST00000011653.9	TSL:1 MANE Select	c.793C>T	p.Arg265Trp	missense	Exon 6 of 10	ENSP00000011653.4	P01730
	CD4	ENST00000541982.5	TSL:1	c.*506C>T		3_prime_UTR	Exon 5 of 5	ENSP00000445167.1	F5H480
	CD4	ENST00000538827.5	TSL:1	n.869C>T		non_coding_transcript_exon	Exon 4 of 4

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

GnomAD2 exomes AF: 0.0191 AC: 4780 AN: 250838 AF XY: 0.0151

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

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: 0 AN: 53420

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5766

European-Non Finnish (NFE) AF: 0.00116 AC: 1293 AN: 1112006

Other (OTH) AF: 0.0166 AC: 1004 AN: 60396

GnomAD4 genome AF: 0.0597 AC: 9083 AN: 152238 Hom.: 834 Cov.: 32 AF XY: 0.0580 AC XY: 4318 AN XY: 74442

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: 48 AN: 3472

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5182

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68022

Other (OTH) AF: 0.0430 AC: 91 AN: 2116

Alfa AF: 0.0243 Hom.: 792

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	1	Okt4 epitope deficiency (2)
-	-	1	CD4-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-2.0
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
Mutation Taster		=91/9	disease causing (ClinVar)

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

Other links and lift over

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