X-136656377-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_000074.3(CD40LG):c.368C>T(p.Ala123Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 1,207,416 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A123E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 0 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.93

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000074.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-136656377-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11168.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3 linkuse as main transcript	c.368C>T	p.Ala123Val	missense_variant	4/5	ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7 linkuse as main transcript	c.368C>T	p.Ala123Val	missense_variant	4/5	1	NM_000074.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111834

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34012

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183016

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67634

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1095528

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361052

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000476

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111888

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34076

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000372

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyper-IgM syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 02, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CD40LG protein function. ClinVar contains an entry for this variant (Variation ID: 423253). This variant has not been reported in the literature in individuals affected with CD40LG-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 123 of the CD40LG protein (p.Ala123Val). This variant disrupts the p.Ala123 amino acid residue in CD40LG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8094231, 10559240, 15623492). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2017

The A123V variant in the CD40LG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However a different missense variant at this same codon (A123E) has been reported in a child with hyper-IgM syndrome (DiSanto et al., 1993). While the diagnosis of hyper-IgM was confirmed by lack of CD40LG seen in stimulated T-cells from this individual, further evidence supporting the pathogenicity of the A123E variant, such as functional studies on this specific variant, were not provided (DiSanto et al., 1993). The A123V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A123V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the information available, we interpret A123V as a variant of uncertain clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

Sift4G

Benign

0.43

Polyphen

1.0

Vest4

0.60

MutPred

0.68

Loss of disorder (P = 0.0807);

MVP

0.97

MPC

1.3

ClinPred

0.76

GERP RS

5.5

Varity_R

0.56

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over