rs104894778

Variant names:

• chrX-136656377-C-A
• rs104894778
• NM_000074.3:c.368C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-136656377-C-A
• chrX-136656377-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Moderate

The NM_000074.3(CD40LG):​c.368C>A​(p.Ala123Glu) 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 Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000819791: Experimental studies have shown that this missense change disrupts CD40LG protein function (PMID:¬†8094231,¬†10559240).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A123V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.93
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000819791: Experimental studies have shown that this missense change disrupts CD40LG protein function (PMID:¬†8094231,¬†10559240).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-136656377-C-A is Pathogenic according to our data. Variant chrX-136656377-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11168.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	NM_000074.3	MANE Select	c.368C>A	p.Ala123Glu	missense	Exon 4 of 5	NP_000065.1	P29965

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.368C>A	p.Ala123Glu	missense	Exon 4 of 5	ENSP00000359663.2	P29965
	CD40LG	ENST00000370628.2	TSL:1	c.346+1947C>A		intron	N/A	ENSP00000359662.2	Q3L8U2
	CD40LG	ENST00000695724.1		c.310C>A	p.Arg104Arg	synonymous	Exon 3 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000681 Hom.: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hyper-IgM syndrome type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.89		Gain of disorder (P = 0.0237)
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.96
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs104894778; hg19: chrX-135738536;