X-136648355-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000074.3(CD40LG):c.107T>G(p.Met36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M36K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.64

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 18 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136648355-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422070.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant X-136648355-T-G is Pathogenic according to our data. Variant chrX-136648355-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3	c.107T>G	p.Met36Arg	missense_variant	1/5	ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7	c.107T>G	p.Met36Arg	missense_variant	1/5	1	NM_000074.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 11, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CD40LG function (PMID: 10559240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CD40LG protein function. ClinVar contains an entry for this variant (Variation ID: 11162). This missense change has been observed in individual(s) with X-linked hyper-IgM syndrome (PMID: 7679206, 15358621). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 36 of the CD40LG protein (p.Met36Arg). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 1993	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Aug 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	0.68	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.99	D;D
Vest4		0.76
MutPred		0.86		Gain of catalytic residue at M36 (P = 0.0101);Gain of catalytic residue at M36 (P = 0.0101);
MVP		1.0
MPC		1.5
ClinPred		0.82	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.92

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: rs104894774; hg19: chrX-135730514;