X-136648355-T-G

Variant names:

• chrX-136648355-T-G
• rs104894774
• NM_000074.3:c.107T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. 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
• Publications: 9 publications found

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]

CD40LG Gene-Disease associations (from GenCC):

• hyper-IgM syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• 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 VariationId is 422070.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 11162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000074.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	NM_000074.3	MANE Select	c.107T>G	p.Met36Arg	missense	Exon 1 of 5	NP_000065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.107T>G	p.Met36Arg	missense	Exon 1 of 5	ENSP00000359663.2
	CD40LG	ENST00000370628.2	TSL:1	c.107T>G	p.Met36Arg	missense	Exon 1 of 4	ENSP00000359662.2
	CD40LG	ENST00000695724.1		c.107T>G	p.Met36Arg	missense	Exon 1 of 4	ENSP00000512122.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000653 Hom.: 0

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

Aug 14, 2018

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CD40LG function (PMID: 10559240). 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked hyper-IgM syndrome (PMID: 7679206, 15358621). ClinVar contains an entry for this variant (Variation ID: 11162). 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.

Feb 11, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.86		Gain of catalytic residue at M36 (P = 0.0101)
MVP		1.0
MPC		1.5
ClinPred		0.82	D
GERP RS		4.5
PromoterAI		0.020	Neutral
Varity_R		0.85
gMVP		0.92
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894774; hg19: chrX-135730514;