X-136648355-T-A

Position:

• chrX-136648355-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000074.3(CD40LG):​c.107T>A​(p.Met36Lys) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain CD40 ligand, membrane form (size 260) in uniprot entity CD40L_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant X-136648355-T-A is Pathogenic according to our data. 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}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.107T>A	p.Met36Lys	missense_variant	1/5	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.107T>A	p.Met36Lys	missense_variant	1/5	1	NM_000074.3	ENSP00000359663	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyper-IgM syndrome type 1 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2020	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 not expected to disrupt CD40LG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Met36 amino acid residue in CD40LG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7679206, 15358621). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CD40LG-related conditions. ClinVar contains an entry for this variant (Variation ID: 422070). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 36 of the CD40LG protein (p.Met36Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2016

The M36K variant in the CD40LG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species, the M36K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (M36R) has been reported in association with hyper-IgM syndrome (Korthauer et al., 1993), supporting the functional importance of this region of the protein. The M36K variant is a strong candidate for a pathogenic variant, however the possibility it my be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.62	D;T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	0.64	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.93	P;P
Vest4		0.68
MutPred		0.77		Gain of ubiquitination at M36 (P = 0.0192);Gain of ubiquitination at M36 (P = 0.0192);
MVP		0.99
MPC		1.5
ClinPred		0.77	D
GERP RS		4.5
Varity_R		0.76
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;