20-46118343-T-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.-1T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 1,613,190 control chromosomes in the GnomAD database, including 461,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48521 hom., cov: 34)
  • Exomes 𝑓: 0.75 (412773 hom.)
• Consequence: CD40 NM_001250.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.192

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=-0.71).
• BP6: Variant 20-46118343-T-C is Benign according to our data. Variant chr20-46118343-T-C is described in ClinVar as [Benign]. Clinvar id is 338569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46118343-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40	NM_001250.6	c.-1T>C		5_prime_UTR_variant	1/9	ENST00000372285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40	ENST00000372285.8	c.-1T>C		5_prime_UTR_variant	1/9	1	NM_001250.6	P1

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120443 AN: 152090 Hom.: 48449 Cov.: 34

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.763

GnomAD3 exomes AF: 0.748 AC: 187810 AN: 251134 Hom.: 71019 AF XY: 0.743 AC XY: 100891 AN XY: 135764

Gnomad AFR exome AF: 0.944

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.569

Gnomad SAS exome AF: 0.748

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.750 AC: 1095784 AN: 1460982 Hom.: 412773 Cov.: 47 AF XY: 0.749 AC XY: 544217 AN XY: 726826

Gnomad4 AFR exome AF: 0.947

Gnomad4 AMR exome AF: 0.803

Gnomad4 ASJ exome AF: 0.721

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.725

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 0.742

GnomAD4 genome AF: 0.792 AC: 120577 AN: 152208 Hom.: 48521 Cov.: 34 AF XY: 0.787 AC XY: 58533 AN XY: 74408

Gnomad4 AFR AF: 0.940

Gnomad4 AMR AF: 0.775

Gnomad4 ASJ AF: 0.728

Gnomad4 EAS AF: 0.569

Gnomad4 SAS AF: 0.735

Gnomad4 FIN AF: 0.724

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.766

Alfa AF: 0.756 Hom.: 56839

Bravo AF: 0.803

Asia WGS AF: 0.729 AC: 2537 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 3 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 20137882, 18287517, 20127135, 21091218, 17344890, 20473910, 23669336, 18097708, 20634952, 24828072, 15731360, 27745838, 29780830, 31373353, 31642196, 23954880) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Apr 09, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	12
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: rs1883832; hg19: chr20-44746982; COSMIC: COSV64847693; COSMIC: COSV64847693;