rs104894769

Variant names:

• chrX-136659093-T-A
• rs104894769
• NM_000074.3:c.464T>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000074.3(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 NM_000074.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.24
• Publications: 10 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 10 ACMG points.

• PM1: In a chain CD40 ligand, soluble form (size 148) in uniprot entity CD40L_HUMAN there are 33 pathogenic changes around while only 12 benign (73%) 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-136659093-T-C is described in ClinVar as Pathogenic. ClinVar VariationId 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 VariationId is 421148.Status of the report is criteria_provided_single_submitter, 1 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.464T>A	p.Leu155Gln	missense	Exon 5 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.464T>A	p.Leu155Gln	missense	Exon 5 of 5	ENSP00000359663.2
	CD40LG	ENST00000370628.2	TSL:1	c.401T>A	p.Leu134Gln	missense	Exon 4 of 4	ENSP00000359662.2
	CD40LG	ENST00000695726.1		n.2432T>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.015	D
Sift4G	Benign	0.085	T
Polyphen		1.0	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
Mutation Taster		=26/74	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: rs104894769; hg19: chrX-135741252;