12-6814296-C-T

Variant names:

• chr12-6814296-C-T
• rs11064416
• NM_000616.5:c.369C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195014.3(CD4):​c.-494C>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 0.0018 in 1,613,462 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (15 hom.)
• Consequence: CD4 NM_001195014.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0860
• Publications: 2 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 (BayesDel_noAF=-0.52).
• BP6: Variant 12-6814296-C-T is Benign according to our data. Variant chr12-6814296-C-T is described in ClinVar as Benign. ClinVar VariationId is 714504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00956 (1454/152160) while in subpopulation AFR AF = 0.0326 (1353/41472). AF 95% confidence interval is 0.0312. There are 19 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195014.3. 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.369C>T	p.Phe123Phe	synonymous	Exon 4 of 10	NP_000607.1	P01730
	CD4	NM_001195014.3		c.-494C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001181943.1
	CD4	NM_001195015.3		c.-464C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001181944.1	B4DT49

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	ENST00000011653.9	TSL:1 MANE Select	c.369C>T	p.Phe123Phe	synonymous	Exon 4 of 10	ENSP00000011653.4	P01730
	CD4	ENST00000541982.5	TSL:1	c.204C>T	p.Phe68Phe	synonymous	Exon 3 of 5	ENSP00000445167.1	F5H480
	CD4	ENST00000538827.5	TSL:1	n.282C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1456 AN: 152042 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00239 AC: 599 AN: 250786 AF XY: 0.00152

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000994 AC: 1453 AN: 1461302 Hom.: 15 Cov.: 32 AF XY: 0.000846 AC XY: 615 AN XY: 726916

African (AFR) AF: 0.0333 AC: 1114 AN: 33474

American (AMR) AF: 0.00226 AC: 101 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5752

European-Non Finnish (NFE) AF: 0.0000918 AC: 102 AN: 1111668

Other (OTH) AF: 0.00207 AC: 125 AN: 60378

GnomAD4 genome AF: 0.00956 AC: 1454 AN: 152160 Hom.: 19 Cov.: 31 AF XY: 0.00891 AC XY: 663 AN XY: 74382

African (AFR) AF: 0.0326 AC: 1353 AN: 41472

American (AMR) AF: 0.00510 AC: 78 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68008

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00333 Hom.: 3

Bravo AF: 0.0110

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.57
PhyloP100		0.086
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11064416; hg19: chr12-6923462;