rs193922136

Variant names:

• chrX-136659390-C-A
• rs193922136
• NM_000074.3:c.761C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-136659390-C-A
• chrX-136659390-C-T

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.761C>A​(p.Thr254Lys) 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. T254M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.84
• Publications: 25 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 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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-136659390-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 35814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant X-136659390-C-A is Pathogenic according to our data. Variant chrX-136659390-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 530671.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.761C>A	p.Thr254Lys	missense	Exon 5 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.761C>A	p.Thr254Lys	missense	Exon 5 of 5	ENSP00000359663.2	P29965
	CD40LG	ENST00000370628.2	TSL:1	c.698C>A	p.Thr233Lys	missense	Exon 4 of 4	ENSP00000359662.2	Q3L8U2
	CD40LG	ENST00000695724.1		c.*379C>A		3_prime_UTR	Exon 4 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.68		Gain of methylation at T254 (P = 0.0172)
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.88
Mutation Taster		=18/82	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: rs193922136; hg19: chrX-135741549; COSMIC: COSV65699024;