12-6816147-G-T

Variant names:

• chr12-6816147-G-T
• rs10849525
• NM_000616.5:c.699G>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.-121G>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 0.00402 in 1,614,150 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (89 hom.)
• Consequence: CD4 NM_001195015.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.139
• Publications: 3 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=-0.88).
• BP6: Variant 12-6816147-G-T is Benign according to our data. Variant chr12-6816147-G-T is described in ClinVar as Benign. ClinVar VariationId is 789805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0681 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.699G>T	p.Thr233Thr	synonymous	Exon 6 of 10	NP_000607.1	P01730
	CD4	NM_001195015.3		c.-121G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 8	NP_001181944.1	B4DT49
	CD4	NM_001195016.3		c.-121G>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.699G>T	p.Thr233Thr	synonymous	Exon 6 of 10	ENSP00000011653.4	P01730
	CD4	ENST00000541982.5	TSL:1	c.*412G>T		3_prime_UTR	Exon 5 of 5	ENSP00000445167.1	F5H480
	CD4	ENST00000538827.5	TSL:1	n.775G>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3127 AN: 152152 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00526 AC: 1322 AN: 251470 AF XY: 0.00363

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00230 AC: 3358 AN: 1461880 Hom.: 89 Cov.: 34 AF XY: 0.00198 AC XY: 1437 AN XY: 727242

African (AFR) AF: 0.0724 AC: 2423 AN: 33478

American (AMR) AF: 0.00418 AC: 187 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000410 AC: 456 AN: 1112006

Other (OTH) AF: 0.00439 AC: 265 AN: 60394

GnomAD4 genome AF: 0.0206 AC: 3136 AN: 152270 Hom.: 96 Cov.: 32 AF XY: 0.0200 AC XY: 1491 AN XY: 74460

African (AFR) AF: 0.0703 AC: 2918 AN: 41522

American (AMR) AF: 0.0103 AC: 158 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00531 Hom.: 3

Bravo AF: 0.0242

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

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	-0.88
CADD	Benign	1.1
DANN	Benign	0.25
PhyloP100		0.14
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: rs10849525; hg19: chr12-6925313;