Genetic Variant CD40LG:p.Tyr169Cys (chrX-136659135-A-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.42

Publications

4 publications found

Variant links:

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

CD40LG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 2 benign, 4 uncertain 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 VariationId is 191254.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.506A>G	p.Tyr169Cys	missense	Exon 5 of 5	NP_000065.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.506A>G	p.Tyr169Cys	missense	Exon 5 of 5	ENSP00000359663.2
CD40LG	ENST00000370628.2	TSL:1	c.443A>G	p.Tyr148Cys	missense	Exon 4 of 4	ENSP00000359662.2
CD40LG	ENST00000695726.1		n.2474A>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.70

BayesDel_noAF

Pathogenic

0.77

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

PhyloP100

6.4

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-8.9

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.86

Gain of catalytic residue at Y169 (P = 0.1044)

MVP

1.0

MPC

1.5

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

0.99

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over