NM_001250.6:c.-1T>C

Variant names:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_001250.6(CD40):c.-1T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.754 (AC=1,216,361) in the gnomAD database across 1,613,190 control chromosomes, including 461,294 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.939. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 48521 hom., cov: 34)

Exomes 𝑓: 0.75 ( 412773 hom. )

Consequence

CD40
NM_001250.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.192

Publications

295 publications found

Variant links:

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

CD40 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001250.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -16 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9386 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001250.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CD40	NM_001250.6	MANE Select	c.-1T>C	5_prime_UTR	Exon 1 of 9	NP_001241.1	P25942-1
CD40	NM_001322421.2		c.-1T>C	5_prime_UTR	Exon 1 of 9	NP_001309350.1
CD40	NM_001302753.2		c.-1T>C	5_prime_UTR	Exon 1 of 9	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CD40	ENST00000372285.8	TSL:1 MANE Select	c.-1T>C	5_prime_UTR	Exon 1 of 9	ENSP00000361359.3	P25942-1
CD40	ENST00000372276.7	TSL:1	c.-1T>C	5_prime_UTR	Exon 1 of 8	ENSP00000361350.3	P25942-2
CD40	ENST00000620709.4	TSL:1	n.-1T>C	5_prime_UTR	Exon 1 of 7	ENSP00000484074.1	A0A087X1D0

Frequencies

GnomAD3 genomes

AF:

0.792

AC:

120443

AN:

152090

Hom.:

48449

Cov.:

show subpopulations

Gnomad AFR

AF:

0.939

Gnomad AMI

AF:

0.759

Gnomad AMR

AF:

0.774

Gnomad ASJ

AF:

0.728

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.736

Gnomad FIN

AF:

0.724

Gnomad MID

AF:

0.725

Gnomad NFE

AF:

0.742

Gnomad OTH

AF:

0.763

GnomAD2 exomes

AF:

0.748

AC:

187810

AN:

251134

AF XY:

0.743

show subpopulations

Gnomad AFR exome

AF:

0.944

Gnomad AMR exome

AF:

0.803

Gnomad ASJ exome

AF:

0.715

Gnomad EAS exome

AF:

0.569

Gnomad FIN exome

AF:

0.721

Gnomad NFE exome

AF:

0.741

Gnomad OTH exome

AF:

0.739

GnomAD4 exome

AF:

0.750

AC:

1095784

AN:

1460982

Hom.:

412773

Cov.:

AF XY:

0.749

AC XY:

544217

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.947

AC:

31709

AN:

33472

American (AMR)

AF:

0.803

AC:

35918

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

18832

AN:

26120

East Asian (EAS)

AF:

0.593

AC:

23536

AN:

39694

South Asian (SAS)

AF:

0.748

AC:

64510

AN:

86230

European-Finnish (FIN)

AF:

0.725

AC:

38681

AN:

53328

Middle Eastern (MID)

AF:

0.705

AC:

3940

AN:

5592

European-Non Finnish (NFE)

AF:

0.750

AC:

833877

AN:

1111466

Other (OTH)

AF:

0.742

AC:

44781

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

14322

28643

42965

57286

71608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20334

40668

61002

81336

101670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.792

AC:

120577

AN:

152208

Hom.:

48521

Cov.:

AF XY:

0.787

AC XY:

58533

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.940

AC:

39056

AN:

41566

American (AMR)

AF:

0.775

AC:

11855

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.728

AC:

2522

AN:

3466

East Asian (EAS)

AF:

0.569

AC:

2926

AN:

5146

South Asian (SAS)

AF:

0.735

AC:

3545

AN:

4820

European-Finnish (FIN)

AF:

0.724

AC:

7670

AN:

10592

Middle Eastern (MID)

AF:

0.724

AC:

213

AN:

294

European-Non Finnish (NFE)

AF:

0.742

AC:

50480

AN:

67994

Other (OTH)

AF:

0.766

AC:

1618

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1258

2516

3774

5032

6290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.764

Hom.:

130704

Bravo

AF:

0.803

Asia WGS

AF:

0.729

AC:

2537

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.615

AC:

75400

AN:

122550

Turkish Variome

AF:

0.686

AC:

4591

AN:

6694

Hom.:

1585

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.599

AC:

5370

AN:

8960

Hom.:

1617

ABraOM SABE-WGS-1171

AF:

0.792

AC:

1854

AN:

2342

Hom.:

743

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyper-IgM syndrome type 3 (4)

not specified (4)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

-0.19

PromoterAI

0.17

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over