rs104894778

chrX-136656377-C-AchrX-136656377-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000074.3(CD40LG):c.368C>A(p.Ala123Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A123V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.93

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-136656377-C-A is Pathogenic according to our data. Variant chrX-136656377-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3	c.368C>A	p.Ala123Glu	missense_variant	4/5	ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7	c.368C>A	p.Ala123Glu	missense_variant	4/5	1	NM_000074.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2020	This variant has been observed in several individuals with X linked hyper-IgM syndrome (XHIM), and has been shown to segregate with disease in one family (PMID: 15623492, 8094231). ClinVar contains an entry for this variant (Variation ID: 11168). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 123 of the CD40LG protein (p.Ala123Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. Experimental studies have shown that this missense change disrupts CD40LG protein function (PMID: 8094231, 10559240). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.89		Gain of disorder (P = 0.0237);
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.96

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: rs104894778; hg19: chrX-135738536;