20-46119308-T-G

Position:

• chr20-46119308-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001250.6(CD40):​c.51+914T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,190 control chromosomes in the GnomAD database, including 47,588 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.79 (47588 hom., cov: 33)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40	NM_001250.6	c.51+914T>G		intron_variant		ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.51+914T>G		intron_variant		1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119431 AN: 152072 Hom.: 47532 Cov.: 33

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.786 AC: 119547 AN: 152190 Hom.: 47588 Cov.: 33 AF XY: 0.780 AC XY: 58003 AN XY: 74388

Gnomad4 AFR AF: 0.918

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.735

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.763

Alfa AF: 0.742 Hom.: 60047

Bravo AF: 0.796

Asia WGS AF: 0.723 AC: 2517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.46

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: rs4810485; hg19: chr20-44747947;