X-136648280-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM1 BP4 BP6_Very_Strong BS1 BS2

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 (★★).

• 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.20

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM1: In a chain CD40 ligand, membrane form (size 260) in uniprot entity CD40L_HUMAN there are 53 pathogenic changes around while only 16 benign (77%) 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3	c.32G>A	p.Arg11Gln	missense_variant	1/5	ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7	c.32G>A	p.Arg11Gln	missense_variant	1/5	1	NM_000074.3	P1

Frequencies

GnomAD3 genomes AF: 0.000234 AC: 26 AN: 111040 Hom.: 0 Cov.: 22 AF XY: 0.000301 AC XY: 10 AN XY: 33270

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

GnomAD3 exomes AF: 0.000147 AC: 27 AN: 183218 Hom.: 0 AF XY: 0.000192 AC XY: 13 AN XY: 67738

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 SAS exome AF: 0.00

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.: 0 Cov.: 28 AF XY: 0.000278 AC XY: 99 AN XY: 356284

Gnomad4 AFR exome AF: 0.0000381

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.0000517

Gnomad4 EAS exome AF: 0.000497

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.000234 AC: 26 AN: 111040 Hom.: 0 Cov.: 22 AF XY: 0.000301 AC XY: 10 AN XY: 33270

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.000480

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000359

Gnomad4 OTH AF: 0.000670

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.000230

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

CD40LG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
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	T
GERP RS		3.9
Varity_R		0.30
gMVP		0.86

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

Other links and lift over

dbSNP: rs145115086; hg19: chrX-135730439; COSMIC: COSV65698277;