X-136648279-C-T

Position:

• chrX-136648279-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000074.3(CD40LG):​c.31C>T​(p.Arg11Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,813 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CD40LG NM_000074.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.06

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136648279-C-T is Pathogenic according to our data. Variant chrX-136648279-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 35812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.31C>T	p.Arg11Ter	stop_gained	1/5	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.31C>T	p.Arg11Ter	stop_gained	1/5	1	NM_000074.3	ENSP00000359663	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089813 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 355573

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 1 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed stop gained c.31C>T (p.Arg11Ter) variant in CD40LG gene has been previously reported in multiple individuals affected with hyper-IgM syndrome (Blaeser et al., 2005; Seyama et al., 1998; Kiani-Alikhan et al., 2012; Kutukculer et al., 2018). Experimental studies showed this variant to affect CD40LG function (Blaeser et al., 2005; Seyama et al., 1998; Kiani-Alikhan et al., 2012). The p.Arg11Ter variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg11Ter in CD40LG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg11Ter) in the CD40LG gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in CD40LG gene have been previously reported to be pathogenic (Etzioni and Ochs, 2004). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 35812). This premature translational stop signal has been observed in individual(s) with X-linked hyper-IgM syndrome (PMID: 9746782, 16169277, 22009004, 30405923). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg11*) in the CD40LG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD40LG are known to be pathogenic (PMID: 15319456). -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 05, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	26
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A
Vest4		0.80
GERP RS		3.9

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: rs193922135; hg19: chrX-135730438; COSMIC: COSV65699150;