rs1126535

Variant names:

• chrX-136648396-T-C
• rs1126535
• NM_000074.3:c.148T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-136648396-T-C
• chrX-136648396-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000074.3(CD40LG):​c.148T>C​(p.Leu50Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,207,132 control chromosomes in the GnomAD database, including 17,805 homozygotes. There are 78,582 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1547 hom., 6545 hem., cov: 22)
  • Exomes 𝑓: 0.20 (16258 hom. 72037 hem.)
• Consequence: CD40LG NM_000074.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.309
• Publications: 49 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-136648396-T-C is Benign according to our data. Variant chrX-136648396-T-C is described in ClinVar as Benign. ClinVar VariationId is 518406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.309 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.36 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.148T>C	p.Leu50Leu	synonymous	Exon 1 of 5	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.148T>C	p.Leu50Leu	synonymous	Exon 1 of 5	ENSP00000359663.2	P29965
	CD40LG	ENST00000370628.2	TSL:1	c.148T>C	p.Leu50Leu	synonymous	Exon 1 of 4	ENSP00000359662.2	Q3L8U2
	CD40LG	ENST00000695724.1		c.148T>C	p.Leu50Leu	synonymous	Exon 1 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 21030 AN: 111467 Hom.: 1543 Cov.: 22

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0539

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.239 AC: 43636 AN: 182396 AF XY: 0.233

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.0874

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.197 AC: 216125 AN: 1095610 Hom.: 16258 Cov.: 30 AF XY: 0.199 AC XY: 72037 AN XY: 361642

African (AFR) AF: 0.148 AC: 3890 AN: 26345

American (AMR) AF: 0.498 AC: 17522 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 2913 AN: 19360

East Asian (EAS) AF: 0.103 AC: 3114 AN: 30194

South Asian (SAS) AF: 0.328 AC: 17766 AN: 54093

European-Finnish (FIN) AF: 0.202 AC: 8157 AN: 40431

Middle Eastern (MID) AF: 0.176 AC: 726 AN: 4126

European-Non Finnish (NFE) AF: 0.182 AC: 152920 AN: 839873

Other (OTH) AF: 0.198 AC: 9117 AN: 46000

GnomAD4 genome AF: 0.189 AC: 21047 AN: 111522 Hom.: 1547 Cov.: 22 AF XY: 0.193 AC XY: 6545 AN XY: 33978

African (AFR) AF: 0.153 AC: 4702 AN: 30797

American (AMR) AF: 0.370 AC: 3896 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 394 AN: 2635

East Asian (EAS) AF: 0.0864 AC: 310 AN: 3589

South Asian (SAS) AF: 0.332 AC: 885 AN: 2668

European-Finnish (FIN) AF: 0.188 AC: 1136 AN: 6039

Middle Eastern (MID) AF: 0.164 AC: 35 AN: 214

European-Non Finnish (NFE) AF: 0.177 AC: 9328 AN: 52837

Other (OTH) AF: 0.213 AC: 324 AN: 1519

Alfa AF: 0.189 Hom.: 17160

Bravo AF: 0.204

EpiCase AF: 0.176

EpiControl AF: 0.171

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyper-IgM syndrome type 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.5
DANN	Benign	0.78
PhyloP100		-0.31
PromoterAI		0.039	Neutral
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: rs1126535; hg19: chrX-135730555; COSMIC: COSV65698528;