rs3765459

chr20-46128768-G-Achr20-46128768-G-C

Variant summary

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

The NM_001250.6(CD40):c.676-114G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,156,138 control chromosomes in the GnomAD database, including 31,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3061 hom., cov: 31)
  • Exomes 𝑓: 0.23 (28211 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.97

Genes affected

CD40 (HGNC:11919): (CD40 molecule) This gene is a member of the TNF-receptor superfamily. The encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3). Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 20-46128768-G-A is Benign according to our data. Variant chr20-46128768-G-A is described in ClinVar as [Benign]. Clinvar id is 1261840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40	NM_001250.6	c.676-114G>A		intron_variant		ENST00000372285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40	ENST00000372285.8	c.676-114G>A		intron_variant		1	NM_001250.6	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27985 AN: 151880 Hom.: 3056 Cov.: 31

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.220 AC: 35321 AN: 160452 Hom.: 4208 AF XY: 0.228 AC XY: 19707 AN XY: 86452

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.308

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.231 AC: 231901 AN: 1004140 Hom.: 28211 Cov.: 13 AF XY: 0.233 AC XY: 119087 AN XY: 510964

Gnomad4 AFR exome AF: 0.0599

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.184 AC: 27995 AN: 151998 Hom.: 3061 Cov.: 31 AF XY: 0.186 AC XY: 13800 AN XY: 74272

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.179

Alfa AF: 0.207 Hom.: 680

Bravo AF: 0.173

Asia WGS AF: 0.228 AC: 794 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 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.077
Dann	Benign	0.75

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: rs3765459; hg19: chr20-44757407; COSMIC: COSV64847756; COSMIC: COSV64847756;