rs3092923

chrX-136659026-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000074.3(CD40LG):c.410-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,206,594 control chromosomes in the GnomAD database, including 15,267 homozygotes. There are 50,475 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5848 hom., 8327 hem., cov: 22)
  • Exomes 𝑓: 0.12 (9419 hom. 42148 hem.)
• Consequence: CD40LG NM_000074.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.331

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-136659026-T-C is Benign according to our data. Variant chrX-136659026-T-C is described in ClinVar as [Benign]. Clinvar id is 518407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136659026-T-C is described in Lovd as [Benign]. Variant chrX-136659026-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3	c.410-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7	c.410-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000074.3	P1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 29594 AN: 110768 Hom.: 5844 Cov.: 22 AF XY: 0.249 AC XY: 8278 AN XY: 33294

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.00438

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.167 AC: 30241 AN: 181473 Hom.: 3469 AF XY: 0.156 AC XY: 10442 AN XY: 66869

Gnomad AFR exome AF: 0.715

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.104

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.116 AC: 126805 AN: 1095772 Hom.: 9419 Cov.: 30 AF XY: 0.117 AC XY: 42148 AN XY: 361532

Gnomad4 AFR exome AF: 0.726

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.0755

Gnomad4 NFE exome AF: 0.0852

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.268 AC: 29654 AN: 110822 Hom.: 5848 Cov.: 22 AF XY: 0.250 AC XY: 8327 AN XY: 33360

Gnomad4 AFR AF: 0.697

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.0652

Gnomad4 NFE AF: 0.0858

Gnomad4 OTH AF: 0.244

Alfa AF: 0.187 Hom.: 2122

Bravo AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.1
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3092923; hg19: chrX-135741185; COSMIC: COSV65698579;