rs3765457

Positions:

• chr20-46128574-A-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.675+216A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 711,102 control chromosomes in the GnomAD database, including 6,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1138 hom., cov: 30)
  • Exomes 𝑓: 0.14 (5727 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.24

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=-0.95).
• BP6: Variant 20-46128574-A-G is Benign according to our data. Variant chr20-46128574-A-G is described in ClinVar as [Benign]. Clinvar id is 1236220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40	NM_001250.6	c.675+216A>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.675+216A>G		intron_variant		1	NM_001250.6	ENSP00000361359	P1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17303 AN: 151844 Hom.: 1137 Cov.: 30

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.118 AC: 15829 AN: 134174 Hom.: 1132 AF XY: 0.123 AC XY: 8854 AN XY: 72082

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0297

Gnomad SAS exome AF: 0.130

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.136 AC: 75804 AN: 559142 Hom.: 5727 Cov.: 5 AF XY: 0.136 AC XY: 41224 AN XY: 302100

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.0646

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.0364

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.114 AC: 17307 AN: 151960 Hom.: 1138 Cov.: 30 AF XY: 0.110 AC XY: 8206 AN XY: 74284

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.0762

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.0312

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.119

Alfa AF: 0.142 Hom.: 1583

Bravo AF: 0.106

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.35
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3765457; hg19: chr20-44757213;