12-6817197-T-C

Position:

• chr12-6817197-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000616.5(CD4):​c.1023T>C​(p.Ser341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,613,520 control chromosomes in the GnomAD database, including 283,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32183 hom., cov: 32)
  • Exomes 𝑓: 0.58 (251612 hom.)
• Consequence: CD4 NM_000616.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.232

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-6817197-T-C is Benign according to our data. Variant chr12-6817197-T-C is described in ClinVar as [Benign]. Clinvar id is 1192706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6817197-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.232 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD4	NM_000616.5	c.1023T>C	p.Ser341=	synonymous_variant	7/10	ENST00000011653.9	NP_000607.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD4	ENST00000011653.9	c.1023T>C	p.Ser341=	synonymous_variant	7/10	1	NM_000616.5	ENSP00000011653	P1
CD4	ENST00000437800.6	n.1261T>C		non_coding_transcript_exon_variant	5/8	2

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97451 AN: 151924 Hom.: 32156 Cov.: 32

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.619

GnomAD3 exomes AF: 0.644 AC: 161626 AN: 250894 Hom.: 53587 AF XY: 0.640 AC XY: 86712 AN XY: 135578

Gnomad AFR exome AF: 0.755

Gnomad AMR exome AF: 0.691

Gnomad ASJ exome AF: 0.583

Gnomad EAS exome AF: 0.928

Gnomad SAS exome AF: 0.711

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.581 AC: 848783 AN: 1461478 Hom.: 251612 Cov.: 52 AF XY: 0.584 AC XY: 424404 AN XY: 727034

Gnomad4 AFR exome AF: 0.757

Gnomad4 AMR exome AF: 0.680

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.906

Gnomad4 SAS exome AF: 0.705

Gnomad4 FIN exome AF: 0.660

Gnomad4 NFE exome AF: 0.545

Gnomad4 OTH exome AF: 0.602

GnomAD4 genome AF: 0.642 AC: 97542 AN: 152042 Hom.: 32183 Cov.: 32 AF XY: 0.650 AC XY: 48326 AN XY: 74330

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.578

Gnomad4 EAS AF: 0.919

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.666

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.621

Alfa AF: 0.585 Hom.: 23816

Bravo AF: 0.644

Asia WGS AF: 0.782 AC: 2722 AN: 3478

EpiCase AF: 0.548

EpiControl AF: 0.554

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.92
CADD	Benign	7.1
DANN	Benign	0.67

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: rs1055141; hg19: chr12-6926363;