20-46118343-T-C

Variant names:

Variant summary

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

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.192

Variant links:

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]

CD40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CD40	NM_001250.6 link	c.-1T>C		5_prime_UTR_variant	Exon 1 of 9	ENST00000372285.8	NP_001241.1	P25942-1A0A0S2Z3C7Q6P2H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285 link	c.-1T>C		5_prime_UTR_variant	Exon 1 of 9	1	NM_001250.6	ENSP00000361359.3		P25942-1

Frequencies

GnomAD3 genomes

AF:

0.792

AC:

120443

AN:

152090

Hom.:

48449

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.749

AC XY:

544217

AN XY:

726826

show subpopulations

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.:

AF XY:

0.787

AC XY:

58533

AN XY:

74408

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyper-IgM syndrome type 3

Benign:4

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 Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 07, 2020	- -
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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 22, 2024	- -
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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

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

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