NM_000074.3:c.410-13T>C

Variant names:

• chrX-136659026-T-C
• rs3092923
• NM_000074.3:c.410-13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000074.3(CD40LG):​c.410-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,206,594 control chromosomes in the GnomAD database, including 15,267 homozygotes. There are 50,475 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5848 hom., 8327 hem., cov: 22)
  • Exomes 𝑓: 0.12 (9419 hom. 42148 hem.)
• Consequence: CD40LG NM_000074.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.331
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-136659026-T-C is Benign according to our data. Variant chrX-136659026-T-C is described in ClinVar as Benign. ClinVar VariationId is 518407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.410-13T>C		intron_variant	Intron 4 of 4	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.410-13T>C		intron_variant	Intron 4 of 4	1	NM_000074.3	ENSP00000359663.2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 29594 AN: 110768 Hom.: 5844 Cov.: 22

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.00438

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.167 AC: 30241 AN: 181473 AF XY: 0.156

Gnomad AFR exome AF: 0.715

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.116 AC: 126805 AN: 1095772 Hom.: 9419 Cov.: 30 AF XY: 0.117 AC XY: 42148 AN XY: 361532

African (AFR) AF: 0.726 AC: 19119 AN: 26331

American (AMR) AF: 0.182 AC: 6410 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 2469 AN: 19362

East Asian (EAS) AF: 0.116 AC: 3501 AN: 30199

South Asian (SAS) AF: 0.234 AC: 12646 AN: 54086

European-Finnish (FIN) AF: 0.0755 AC: 3045 AN: 40339

Middle Eastern (MID) AF: 0.229 AC: 943 AN: 4126

European-Non Finnish (NFE) AF: 0.0852 AC: 71601 AN: 840115

Other (OTH) AF: 0.154 AC: 7071 AN: 46017

GnomAD4 genome AF: 0.268 AC: 29654 AN: 110822 Hom.: 5848 Cov.: 22 AF XY: 0.250 AC XY: 8327 AN XY: 33360

African (AFR) AF: 0.697 AC: 21124 AN: 30312

American (AMR) AF: 0.178 AC: 1868 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 364 AN: 2633

East Asian (EAS) AF: 0.101 AC: 359 AN: 3542

South Asian (SAS) AF: 0.226 AC: 596 AN: 2641

European-Finnish (FIN) AF: 0.0652 AC: 393 AN: 6023

Middle Eastern (MID) AF: 0.241 AC: 51 AN: 212

European-Non Finnish (NFE) AF: 0.0858 AC: 4526 AN: 52756

Other (OTH) AF: 0.244 AC: 370 AN: 1515

Alfa AF: 0.187 Hom.: 2122

Bravo AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyper-IgM syndrome type 1 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.48
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3092923; hg19: chrX-135741185; COSMIC: COSV65698579;