12-6800222-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000616.5(CD4):c.49+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 1,612,746 control chromosomes in the GnomAD database, including 695,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67476 hom., cov: 28)
  • Exomes 𝑓: 0.93 (628424 hom.)
• Consequence: CD4 NM_000616.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-6800222-A-G is Benign according to our data. Variant chr12-6800222-A-G is described in ClinVar as [Benign]. Clinvar id is 1192705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD4	NM_000616.5	c.49+35A>G		intron_variant		ENST00000011653.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD4	ENST00000011653.9	c.49+35A>G		intron_variant		1	NM_000616.5	P1

Frequencies

GnomAD3 genomes AF: 0.942 AC: 142895 AN: 151718 Hom.: 67426 Cov.: 28

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.948

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.955

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.944

GnomAD3 exomes AF: 0.920 AC: 231122 AN: 251308 Hom.: 107100 AF XY: 0.928 AC XY: 126004 AN XY: 135850

Gnomad AFR exome AF: 0.986

Gnomad AMR exome AF: 0.743

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.976

Gnomad FIN exome AF: 0.950

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.923

GnomAD4 exome AF: 0.927 AC: 1353678 AN: 1460910 Hom.: 628424 Cov.: 37 AF XY: 0.929 AC XY: 675070 AN XY: 726828

Gnomad4 AFR exome AF: 0.988

Gnomad4 AMR exome AF: 0.757

Gnomad4 ASJ exome AF: 0.933

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.976

Gnomad4 FIN exome AF: 0.948

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.933

GnomAD4 genome AF: 0.942 AC: 143003 AN: 151836 Hom.: 67476 Cov.: 28 AF XY: 0.943 AC XY: 69977 AN XY: 74186

Gnomad4 AFR AF: 0.986

Gnomad4 AMR AF: 0.856

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.980

Gnomad4 FIN AF: 0.955

Gnomad4 NFE AF: 0.926

Gnomad4 OTH AF: 0.945

Alfa AF: 0.929 Hom.: 11425

Bravo AF: 0.933

Asia WGS AF: 0.988 AC: 3435 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. Only high quality variants are reported. -

Immunodeficiency 79 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	9.0
Dann	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs2365568; hg19: chr12-6909388;