Genetic Variant NM_000616.5:c.49+35A>G (chr12-6800222-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.42

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CD4	NM_000616.5 link	c.49+35A>G		intron_variant	Intron 2 of 9	ENST00000011653.9	NP_000607.1	P01730B4DT49A0A4Y5UGE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD4	ENST00000011653.9 link	c.49+35A>G		intron_variant	Intron 2 of 9	1	NM_000616.5	ENSP00000011653.4		P01730

Frequencies

GnomAD3 genomes

AF:

0.942

AC:

142895

AN:

151718

Hom.:

67426

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.929

AC XY:

675070

AN XY:

726828

show subpopulations

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.:

AF XY:

0.943

AC XY:

69977

AN XY:

74186

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. 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

-0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over