rs786205606

Variant names:

• chrX-136659135-A-G
• rs786205606
• NM_000074.3:c.506A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000074.3(CD40LG):​c.506A>G​(p.Tyr169Cys) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.42

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 topological_domain Extracellular (size 214) in uniprot entity CD40L_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-136659135-A-G is Pathogenic according to our data. Variant chrX-136659135-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.506A>G	p.Tyr169Cys	missense_variant	Exon 5 of 5	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.506A>G	p.Tyr169Cys	missense_variant	Exon 5 of 5	1	NM_000074.3	ENSP00000359663.2

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

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.86		Gain of catalytic residue at Y169 (P = 0.1044);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.99

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: rs786205606; hg19: chrX-135741294;