rs104894769

Positions:

• chrX-136659093-T-A
• chrX-136659093-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000370629.7(CD40LG):​c.464T>A​(p.Leu155Gln) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L155P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CD40LG ENST00000370629.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.24

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 chain CD40 ligand, soluble form (size 148) in uniprot entity CD40L_HUMAN there are 53 pathogenic changes around while only 14 benign (79%) in ENST00000370629.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136659093-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11160.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant X-136659093-T-A is Pathogenic according to our data. Variant chrX-136659093-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.464T>A	p.Leu155Gln	missense_variant	5/5	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.464T>A	p.Leu155Gln	missense_variant	5/5	1	NM_000074.3	ENSP00000359663	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.015	D;T
Sift4G	Benign	0.085	T;T
Polyphen		1.0	D;D
Vest4		0.31
MutPred		0.81		Loss of stability (P = 0.017);.;
MVP		0.96
MPC		1.3
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.80
gMVP		0.84

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: rs104894769; hg19: chrX-135741252;