20-46118303-C-T

Variant names:

• chr20-46118303-C-T
• rs11569301
• ENST00000620709.4:n.-41C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000946602.1(CD40):​c.-41C>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 0.00554 in 1,600,012 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (241 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (205 hom.)
• Consequence: CD40 ENST00000946602.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.419
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-46118303-C-T is Benign according to our data. Variant chr20-46118303-C-T is described in ClinVar as Benign. ClinVar VariationId is 338568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000946602.1. 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.-41C>T		upstream_gene	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.-41C>T		upstream_gene	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.-41C>T		upstream_gene	N/A	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000620709.4	TSL:1	n.-41C>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000484074.1	A0A087X1D0
	CD40	ENST00000620709.4	TSL:1	n.-41C>T		5_prime_UTR	Exon 1 of 7	ENSP00000484074.1	A0A087X1D0
	CD40	ENST00000946602.1		c.-41C>T		5_prime_UTR	Exon 1 of 9	ENSP00000616661.1

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4534 AN: 152200 Hom.: 240 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.00774 AC: 1927 AN: 248962 AF XY: 0.00551

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00299 AC: 4324 AN: 1447694 Hom.: 205 Cov.: 28 AF XY: 0.00252 AC XY: 1817 AN XY: 720986

African (AFR) AF: 0.104 AC: 3460 AN: 33154

American (AMR) AF: 0.00605 AC: 270 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

Middle Eastern (MID) AF: 0.00356 AC: 17 AN: 4780

European-Non Finnish (NFE) AF: 0.000145 AC: 160 AN: 1101024

Other (OTH) AF: 0.00681 AC: 408 AN: 59888

GnomAD4 genome AF: 0.0298 AC: 4540 AN: 152318 Hom.: 241 Cov.: 33 AF XY: 0.0287 AC XY: 2136 AN XY: 74476

African (AFR) AF: 0.104 AC: 4326 AN: 41552

American (AMR) AF: 0.00902 AC: 138 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

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

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68036

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0125 Hom.: 39

Bravo AF: 0.0334

Asia WGS AF: 0.00375 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyper-IgM syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.1
DANN	Benign	0.59
PhyloP100		0.42
PromoterAI		0.029	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11569301; hg19: chr20-44746942;