chr20-46118277-G-T

Variant names:

• chr20-46118277-G-T
• rs575088069
• ENST00000890862.1:c.-67G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000890862.1(CD40):​c.-67G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00003 in 1,433,448 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CD40 ENST00000890862.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.191
• Publications: 1 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000118 (18/152360) while in subpopulation AFR AF = 0.000433 (18/41598). AF 95% confidence interval is 0.000279. There are 1 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000890862.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	NM_001250.6	MANE Select	c.-67G>T		upstream_gene	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.-67G>T		upstream_gene	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.-67G>T		upstream_gene	N/A	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000890862.1		c.-67G>T		5_prime_UTR	Exon 1 of 9	ENSP00000560921.1
	CD40	ENST00000890865.1		c.-67G>T		5_prime_UTR	Exon 1 of 9	ENSP00000560924.1
	CD40	ENST00000890867.1		c.-67G>T		5_prime_UTR	Exon 1 of 9	ENSP00000560926.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 25 AN: 1281088 Hom.: 0 Cov.: 18 AF XY: 0.0000232 AC XY: 15 AN XY: 646330

African (AFR) AF: 0.000815 AC: 24 AN: 29448

American (AMR) AF: 0.00 AC: 0 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24936

East Asian (EAS) AF: 0.00 AC: 0 AN: 38900

South Asian (SAS) AF: 0.00 AC: 0 AN: 82316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 952556

Other (OTH) AF: 0.0000184 AC: 1 AN: 54416

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152360 Hom.: 1 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74498

African (AFR) AF: 0.000433 AC: 18 AN: 41598

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyper-IgM syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.2
DANN	Benign	0.86
PhyloP100		0.19
PromoterAI		0.059	Neutral

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: rs575088069; hg19: chr20-44746916;