rs11575982

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM1BP4_StrongBP6_ModerateBS1BS2

The NM_000074.3(CD40LG):c.542G>A(p.Arg181Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,209,778 control chromosomes in the GnomAD database, including 6 homozygotes. There are 521 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., 24 hem., cov: 22)

Exomes 𝑓: 0.00086 ( 6 hom. 497 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.340

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hyper-IgM syndrome type 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

CD40LG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PM1

In a chain CD40 ligand, soluble form (size 148) in uniprot entity CD40L_HUMAN there are 33 pathogenic changes around while only 12 benign (73%) in NM_000074.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0032913983).

BP6

Variant X-136659171-G-A is Benign according to our data. Variant chrX-136659171-G-A is described in ClinVar as Benign. ClinVar VariationId is 530672.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000518 (58/111924) while in subpopulation SAS AF = 0.018 (48/2667). AF 95% confidence interval is 0.0139. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3 link	c.542G>A	p.Arg181Gln	missense_variant	Exon 5 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.542G>A	p.Arg181Gln	missense_variant	Exon 5 of 5	1	NM_000074.3	ENSP00000359663.2		P29965

Frequencies

GnomAD3 genomes

AF:

0.000510

AC:

AN:

111870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00195

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00183

AC:

336

AN:

183179

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00195

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000612

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.000861

AC:

945

AN:

1097854

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

497

AN XY:

363214

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26395

American (AMR)

AF:

0.0000568

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00149

AC:

AN:

30203

South Asian (SAS)

AF:

0.0146

AC:

791

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

841773

Other (OTH)

AF:

0.00161

AC:

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000518

AC:

AN:

111924

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

AN XY:

34088

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30829

American (AMR)

AF:

0.00

AC:

AN:

10565

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00196

AC:

AN:

3570

South Asian (SAS)

AF:

0.0180

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53161

Other (OTH)

AF:

0.00

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000131

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.00227

AC:

276

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyper-IgM syndrome type 1

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;T

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.34

N;.

PhyloP100

-0.34

PrimateAI

Benign

0.22

PROVEAN

Benign

0.53

N;N

REVEL

Benign

0.11

Sift

Benign

0.17

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.12

B;B

Vest4

0.051

MutPred

0.38

Loss of sheet (P = 0.0817);.;

MVP

0.51

MPC

0.51

ClinPred

0.012

GERP RS

1.9

Varity_R

0.10

gMVP

0.28

Mutation Taster

=97/3

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over