rs2076094894

Variant names:

• chrX-136648321-A-G
• rs2076094894
• NM_000074.3:c.73A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000074.3(CD40LG):​c.73A>G​(p.Met25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000459 in 1,089,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 0 hem.)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2641195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.73A>G	p.Met25Val	missense_variant	Exon 1 of 5	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.73A>G	p.Met25Val	missense_variant	Exon 1 of 5	1	NM_000074.3	ENSP00000359663.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000459 AC: 5 AN: 1089566 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 355190

African (AFR) AF: 0.00 AC: 0 AN: 26222

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 53934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4109

European-Non Finnish (NFE) AF: 0.00000599 AC: 5 AN: 834238

Other (OTH) AF: 0.00 AC: 0 AN: 45846

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 1 Uncertain:1

Feb 18, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with valine at codon 25 of the CD40LG protein (p.Met25Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CD40LG-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T;T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.32	T;T
Polyphen		0.29	B;B
Vest4		0.30
MutPred		0.60		Loss of ubiquitination at K22 (P = 0.1066);Loss of ubiquitination at K22 (P = 0.1066);
MVP		0.81
MPC		0.46
ClinPred		0.25	T
GERP RS		3.2
PromoterAI		0.015	Neutral
Varity_R		0.32
gMVP		0.71
Mutation Taster		=91/9	polymorphism

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: rs2076094894; hg19: chrX-135730480;