Genetic Variant CD40LG:p.Ala13Ala (chrX-136648287-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_000074.3(CD40LG):c.39G>A(p.Ala13Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,200,025 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 15 hem. )

Consequence

CD40LG
NM_000074.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.811

Publications

0 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-136648287-G-A is Benign according to our data. Variant chrX-136648287-G-A is described in ClinVar as [Benign]. Clinvar id is 1169681.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.811 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000072 (8/111092) while in subpopulation AMR AF = 0.000287 (3/10443). AF 95% confidence interval is 0.0000777. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3 link	c.39G>A	p.Ala13Ala	synonymous_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.39G>A	p.Ala13Ala	synonymous_variant	Exon 1 of 5	1	NM_000074.3	ENSP00000359663.2		P29965

Frequencies

GnomAD3 genomes

AF:

0.0000720

AC:

AN:

111092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000287

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:

0.0000377

Gnomad OTH

AF:

0.000673

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

183221

AF XY:

0.0000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000723

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000275

AC:

AN:

1088933

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

354619

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26217

American (AMR)

AF:

0.0000568

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19334

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30156

South Asian (SAS)

AF:

0.0000927

AC:

AN:

53924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.0000240

AC:

AN:

833680

Other (OTH)

AF:

0.0000218

AC:

AN:

45798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000720

AC:

AN:

111092

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33334

show subpopulations

African (AFR)

AF:

0.0000655

AC:

AN:

30528

American (AMR)

AF:

0.000287

AC:

AN:

10443

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5895

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

52999

Other (OTH)

AF:

0.000673

AC:

AN:

1485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyper-IgM syndrome type 1

Benign:1

Oct 24, 2024

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

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.0

(source)

DANN

Benign

0.39

PhyloP100

0.81

PromoterAI

-0.010

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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.

X-136648287-G-A

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