rs148594123

Positions:

• chrX-136659284-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000074.3(CD40LG):​c.655G>A​(p.Gly219Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,209,678 control chromosomes in the GnomAD database, including 122 homozygotes. There are 5,855 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (6 hom., 336 hem., cov: 23)
  • Exomes 𝑓: 0.016 (116 hom. 5519 hem.)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000074.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006652802).
• BP6: Variant X-136659284-G-A is Benign according to our data. Variant chrX-136659284-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136659284-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1122/112015) while in subpopulation NFE AF= 0.0151 (801/53154). AF 95% confidence interval is 0.0142. There are 6 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40LG	NM_000074.3	c.655G>A	p.Gly219Arg	missense_variant	5/5	ENST00000370629.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40LG	ENST00000370629.7	c.655G>A	p.Gly219Arg	missense_variant	5/5	1	NM_000074.3	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1120 AN: 111961 Hom.: 6 Cov.: 23 AF XY: 0.00984 AC XY: 336 AN XY: 34159

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00613

Gnomad ASJ AF: 0.00340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00295

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.00468

GnomAD3 exomes AF: 0.0111 AC: 2024 AN: 182591 Hom.: 16 AF XY: 0.0109 AC XY: 732 AN XY: 67227

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00391

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00533

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.0156 AC: 17075 AN: 1097663 Hom.: 116 Cov.: 31 AF XY: 0.0152 AC XY: 5519 AN XY: 363053

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.00258

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00608

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0100 AC: 1122 AN: 112015 Hom.: 6 Cov.: 23 AF XY: 0.00982 AC XY: 336 AN XY: 34223

Gnomad4 AFR AF: 0.00259

Gnomad4 AMR AF: 0.00613

Gnomad4 ASJ AF: 0.00340

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.0247

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.00462

Alfa AF: 0.0139 Hom.: 603

Bravo AF: 0.00832

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0222 AC: 64

ESP6500AA AF: 0.00261 AC: 10

ESP6500EA AF: 0.0171 AC: 115

ExAC AF: 0.0113 AC: 1372

EpiCase AF: 0.0141

EpiControl AF: 0.0133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2016	Variant summary: The CD40LG c.655G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Arg. 3/5 in-silico tools predict this variant to be damaging. In vitro functional studies suggest that G219R has decreased ligand binding and decreased capacity to activate B cells. However, the single expression of G219R protein has no or only minor effects in vivo as shown by an asymptomatic carrier of G219R who has normal values of serum IgA and IgM and normal B-cell subpopulations (Rigaud 2011). These functional studies suggest that this variant is a functional polymorphism.This variant was found in 992/88003 control chromosomes (at least 7 homozygotes and 388 hemizygotes) at a frequency of 0.0112723, which is about 7 times the maximal expected frequency of a pathogenic CD40LG allele (0.0015811) for HIGM1, suggesting this variant is benign. The variant has been reported in patients with hyper IgM syndrome, non-X-linked HIGM, X-linked variable immunodeficiency, and hypogammaglobulinemia, However, some of these patients had other probable disease causing mutations in cis (Gln232X; Lin 1996) or in another gene (XIAP G466X; Rigaud 2011), or unaffected compound heterozygous or hemizygous family members (lack of segregation with disease; Martinez-Martinez 2012 and Rigaud 2011), suggesting that this variant itself is not pathogenic in isolation. Taken together, this variant is not disease causing in isolation but may play a contributory role in certain backgrounds, and therefore is classified as benign. -

Hyper-IgM syndrome type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;D
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Uncertain	-0.0033	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.069	T;T
Polyphen		0.43	B;D
Vest4		0.054
MutPred		0.44		Loss of ubiquitination at K216 (P = 0.0312);.;
MPC		0.63
ClinPred		0.027	T
GERP RS		2.7
Varity_R		0.44
gMVP		0.76

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: rs148594123; hg19: chrX-135741443; COSMIC: COSV65698573;