X-136648280-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1BP4BP6_Very_StrongBS1BS2

The NM_000074.3(CD40LG):c.32G>A(p.Arg11Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000265 in 1,201,660 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 10 hem., cov: 22)

Exomes 𝑓: 0.00027 ( 0 hom. 99 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.20

Variant links:

Genes affected

CD40LG (HGNC:11935): (CD40 ligand) The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]

CD40LG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PM1

In a chain CD40 ligand, membrane form (size 260) in uniprot entity CD40L_HUMAN there are 54 pathogenic changes around while only 17 benign (76%) in NM_000074.3

BP4

Computational evidence support a benign effect (MetaRNN=0.35679162).

BP6

Variant X-136648280-G-A is Benign according to our data. Variant chrX-136648280-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 746752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136648280-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000234 (26/111040) while in subpopulation AMR AF = 0.00048 (5/10416). AF 95% confidence interval is 0.000234. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position FAILED quality control check.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3 link	c.32G>A	p.Arg11Gln	missense_variant	Exon 1 of 5	ENST00000370629.7	NP_000065.1	P29965

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7 link	c.32G>A	p.Arg11Gln	missense_variant	Exon 1 of 5	1	NM_000074.3	ENSP00000359663.2		P29965

Frequencies

GnomAD3 genomes

AF:

0.000234

AC:

AN:

111040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000480

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:

0.000359

Gnomad OTH

AF:

0.000670

GnomAD2 exomes

AF:

0.000147

AC:

AN:

183218

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000269

AC:

293

AN:

1090620

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

AN XY:

356284

show subpopulations

Gnomad4 AFR exome

AF:

0.0000381

AC:

AN:

26249

Gnomad4 AMR exome

AF:

0.0000852

AC:

AN:

35195

Gnomad4 ASJ exome

AF:

0.0000517

AC:

AN:

19345

Gnomad4 EAS exome

AF:

0.000497

AC:

AN:

30165

Gnomad4 SAS exome

AF:

0.0000371

AC:

AN:

53957

Gnomad4 FIN exome

AF:

0.0000247

AC:

AN:

40512

Gnomad4 NFE exome

AF:

0.000317

AC:

265

AN:

835213

Gnomad4 Remaining exome

AF:

0.000109

AC:

AN:

45869

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<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:

0.000234

AC:

AN:

111040

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

AN XY:

33270

show subpopulations

Gnomad4 AFR

AF:

0.0000327

AC:

0.0000327397

AN:

0.0000327397

Gnomad4 AMR

AF:

0.000480

AC:

0.000480031

AN:

0.000480031

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000359

AC:

0.000358653

AN:

0.000358653

Gnomad4 OTH

AF:

0.000670

AC:

0.000669792

AN:

0.000669792

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<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:

0.000182

Hom.:

Bravo

AF:

0.000230

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyper-IgM syndrome type 1

Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CD40LG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;T

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.8

L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.77

N;N

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.073

T;T

Polyphen

1.0

D;D

Vest4

0.18

MVP

0.78

MPC

1.3

ClinPred

0.088

GERP RS

3.9

Varity_R

0.30

gMVP

0.86

Mutation Taster

=99/1

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over