rs11569343

Positions:

• chr20-46129175-C-G

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.*135C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 962,462 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (149 hom., cov: 32)
  • Exomes 𝑓: 0.042 (891 hom.)
• Consequence: CD40 NM_001250.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.169

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=-0.81).
• BP6: Variant 20-46129175-C-G is Benign according to our data. Variant chr20-46129175-C-G is described in ClinVar as [Benign]. Clinvar id is 338579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40	NM_001250.6	c.*135C>G		3_prime_UTR_variant	9/9	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.*135C>G		3_prime_UTR_variant	9/9	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5485 AN: 152190 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.00970

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0540

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0371 AC: 6047 AN: 162882 Hom.: 155 AF XY: 0.0377 AC XY: 3350 AN XY: 88828

Gnomad AFR exome AF: 0.00966

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.000162

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.0665

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0425 AC: 34426 AN: 810156 Hom.: 891 Cov.: 11 AF XY: 0.0419 AC XY: 17725 AN XY: 423042

Gnomad4 AFR exome AF: 0.00915

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.0371

Gnomad4 EAS exome AF: 0.0000587

Gnomad4 SAS exome AF: 0.0243

Gnomad4 FIN exome AF: 0.0649

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0360 AC: 5483 AN: 152306 Hom.: 149 Cov.: 32 AF XY: 0.0354 AC XY: 2637 AN XY: 74472

Gnomad4 AFR AF: 0.00969

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.0377

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0648

Gnomad4 NFE AF: 0.0539

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0456 Hom.: 38

Bravo AF: 0.0312

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Hyper-IgM syndrome type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.86
DANN	Benign	0.59

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: rs11569343; hg19: chr20-44757814;