Genetic Variant NM_000074.3:c.464T>C (chrX-136659093-T-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000074.3(CD40LG):c.464T>C(p.Leu155Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L155Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.24

Publications

10 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

CD40LG links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 421148.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant X-136659093-T-C is Pathogenic according to our data. 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.

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.464T>C	p.Leu155Pro	missense	Exon 5 of 5	NP_000065.1	P29965

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.464T>C	p.Leu155Pro	missense	Exon 5 of 5	ENSP00000359663.2	P29965
CD40LG	ENST00000370628.2	TSL:1	c.401T>C	p.Leu134Pro	missense	Exon 4 of 4	ENSP00000359662.2	Q3L8U2
CD40LG	ENST00000695724.1		c.*82T>C		3_prime_UTR	Exon 4 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyper-IgM syndrome type 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

PhyloP100

4.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.73

Sift

Uncertain

0.012

Sift4G

Benign

0.061

Polyphen

1.0

Vest4

0.64

MutPred

0.84

Loss of stability (P = 0.0075)

MVP

1.0

MPC

1.7

ClinPred

0.93

GERP RS

4.3

Varity_R

0.97

gMVP

0.93

Mutation Taster

=43/57

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over