12-6819581-T-C

Variant names:

• chr12-6819581-T-C
• rs3213427
• NM_000616.5:c.*252T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000616.5(CD4):​c.*252T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 547,690 control chromosomes in the GnomAD database, including 43,497 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10824 hom., cov: 33)
  • Exomes 𝑓: 0.39 (32673 hom.)
• Consequence: CD4 NM_000616.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.166
• Publications: 14 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	NM_000616.5	MANE Select	c.*252T>C		3_prime_UTR	Exon 10 of 10	NP_000607.1
	CD4	NM_001382707.1		c.*252T>C		3_prime_UTR	Exon 11 of 11	NP_001369636.1
	CD4	NM_001382714.1		c.*252T>C		3_prime_UTR	Exon 9 of 9	NP_001369643.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	ENST00000011653.9	TSL:1 MANE Select	c.*252T>C		3_prime_UTR	Exon 10 of 10	ENSP00000011653.4
	CD4	ENST00000437800.6	TSL:2	n.1867T>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54964 AN: 151964 Hom.: 10828 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.392 AC: 154984 AN: 395608 Hom.: 32673 Cov.: 2 AF XY: 0.387 AC XY: 80922 AN XY: 209018

African (AFR) AF: 0.254 AC: 2791 AN: 10998

American (AMR) AF: 0.355 AC: 5803 AN: 16360

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 5116 AN: 11978

East Asian (EAS) AF: 0.0998 AC: 2635 AN: 26402

South Asian (SAS) AF: 0.296 AC: 12740 AN: 42986

European-Finnish (FIN) AF: 0.347 AC: 9013 AN: 25966

Middle Eastern (MID) AF: 0.380 AC: 641 AN: 1686

European-Non Finnish (NFE) AF: 0.454 AC: 107309 AN: 236494

Other (OTH) AF: 0.393 AC: 8936 AN: 22738

GnomAD4 genome AF: 0.362 AC: 54983 AN: 152082 Hom.: 10824 Cov.: 33 AF XY: 0.353 AC XY: 26228 AN XY: 74336

African (AFR) AF: 0.255 AC: 10584 AN: 41484

American (AMR) AF: 0.373 AC: 5695 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1464 AN: 3462

East Asian (EAS) AF: 0.0829 AC: 429 AN: 5176

South Asian (SAS) AF: 0.281 AC: 1356 AN: 4820

European-Finnish (FIN) AF: 0.337 AC: 3561 AN: 10574

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.449 AC: 30538 AN: 67962

Other (OTH) AF: 0.382 AC: 809 AN: 2116

Alfa AF: 0.414 Hom.: 13793

Bravo AF: 0.359

Asia WGS AF: 0.219 AC: 760 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.7
DANN	Benign	0.85
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3213427; hg19: chr12-6928747;