NM_000616.5:c.1023T>C

Variant names:

• chr12-6817197-T-C
• rs1055141
• NM_000616.5:c.1023T>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.Ser341Ser) 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 rank	MANE	Protein	UniProt
CD4	NM_000616.5	c.1023T>C	p.Ser341Ser	synonymous_variant	Exon 7 of 10	ENST00000011653.9	NP_000607.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD4	ENST00000011653.9	c.1023T>C	p.Ser341Ser	synonymous_variant	Exon 7 of 10	1	NM_000616.5	ENSP00000011653.4
CD4	ENST00000437800.6	n.1261T>C		non_coding_transcript_exon_variant	Exon 5 of 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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Immunodeficiency 79 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;