20-46128768-G-T

Variant names:

• chr20-46128768-G-T
• rs3765459
• NM_001250.6:c.676-114G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001250.6(CD40):​c.676-114G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000994 in 1,005,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hyper-IgM syndrome type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.676-114G>T		intron_variant	Intron 8 of 8	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.676-114G>T		intron_variant	Intron 8 of 8	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.94e-7 AC: 1 AN: 1005968 Hom.: 0 Cov.: 13 AF XY: 0.00000195 AC XY: 1 AN XY: 511862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24706

American (AMR) AF: 0.00 AC: 0 AN: 36742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20948

East Asian (EAS) AF: 0.00 AC: 0 AN: 35304

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4872

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 727604

Other (OTH) AF: 0.00 AC: 0 AN: 45010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.050
DANN	Benign	0.69
PhyloP100		-2.0

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

Other links and lift over

dbSNP: rs3765459; hg19: chr20-44757407;