chrX-136649989-G-A

Variant names:

• chrX-136649989-G-A
• rs5930973
• NM_000074.3:c.157-277G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000074.3(CD40LG):​c.157-277G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 112,392 control chromosomes in the GnomAD database, including 92 homozygotes. There are 1,161 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.038 (92 hom., 1161 hem., cov: 23)
• Consequence: CD40LG NM_000074.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.142
• Publications: 9 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-136649989-G-A is Benign according to our data. Variant chrX-136649989-G-A is described in ClinVar as Benign. ClinVar VariationId is 1282887.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

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.157-277G>A		intron	N/A	NP_000065.1	P29965

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.157-277G>A		intron	N/A	ENSP00000359663.2	P29965
	CD40LG	ENST00000370628.2	TSL:1	c.157-277G>A		intron	N/A	ENSP00000359662.2	Q3L8U2
	CD40LG	ENST00000695724.1		c.157-277G>A		intron	N/A	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 4256 AN: 112337 Hom.: 92 Cov.: 23

Gnomad AFR AF: 0.00843

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0317

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0379 AC: 4256 AN: 112392 Hom.: 92 Cov.: 23 AF XY: 0.0336 AC XY: 1161 AN XY: 34586

African (AFR) AF: 0.00841 AC: 261 AN: 31025

American (AMR) AF: 0.0210 AC: 224 AN: 10691

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 55 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3607

South Asian (SAS) AF: 0.00327 AC: 9 AN: 2756

European-Finnish (FIN) AF: 0.0472 AC: 286 AN: 6059

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0631 AC: 3357 AN: 53169

Other (OTH) AF: 0.0314 AC: 48 AN: 1531

Alfa AF: 0.0472 Hom.: 1100

Bravo AF: 0.0355

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.19
DANN	Benign	0.54
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs5930973; hg19: chrX-135732148;