X-136648280-G-C

Variant names:

• chrX-136648280-G-C
• NM_000074.3:c.32G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000074.3(CD40LG):​c.32G>C​(p.Arg11Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000917 in 1,090,623 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain CD40 ligand, membrane form (size 260) in uniprot entity CD40L_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24103928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.32G>C	p.Arg11Pro	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.32G>C	p.Arg11Pro	missense_variant	Exon 1 of 5	1	NM_000074.3	ENSP00000359663.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090623 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 356285

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.39	T;T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.20	B;B
Vest4		0.27
MutPred		0.48		Gain of glycosylation at R11 (P = 0.007);Gain of glycosylation at R11 (P = 0.007);
MVP		0.63
MPC		0.73
ClinPred		0.40	T
GERP RS		3.9
Varity_R		0.35
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135730439;