NM_000074.3:c.32G>A

Variant names:

• chrX-136648280-G-A
• rs145115086
• NM_000074.3:c.32G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_000074.3(CD40LG):​c.32G>A​(p.Arg11Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000265 in 1,201,660 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 10 hem., cov: 22)
  • Exomes 𝑓: 0.00027 (0 hom. 99 hem.)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.20
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35679162).
• BP6: Variant X-136648280-G-A is Benign according to our data. Variant chrX-136648280-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 746752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000234 (26/111040) while in subpopulation AMR AF = 0.00048 (5/10416). AF 95% confidence interval is 0.000234. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

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.32G>A	p.Arg11Gln	missense	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.32G>A	p.Arg11Gln	missense	Exon 1 of 5	ENSP00000359663.2	P29965
	CD40LG	ENST00000370628.2	TSL:1	c.32G>A	p.Arg11Gln	missense	Exon 1 of 4	ENSP00000359662.2	Q3L8U2
	CD40LG	ENST00000695724.1		c.32G>A	p.Arg11Gln	missense	Exon 1 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes AF: 0.000234 AC: 26 AN: 111040 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000359

Gnomad OTH AF: 0.000670

GnomAD2 exomes AF: 0.000147 AC: 27 AN: 183218 AF XY: 0.000192

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 293 AN: 1090620 Hom.: 0 Cov.: 28 AF XY: 0.000278 AC XY: 99 AN XY: 356284

African (AFR) AF: 0.0000381 AC: 1 AN: 26249

American (AMR) AF: 0.0000852 AC: 3 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19345

East Asian (EAS) AF: 0.000497 AC: 15 AN: 30165

South Asian (SAS) AF: 0.0000371 AC: 2 AN: 53957

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4115

European-Non Finnish (NFE) AF: 0.000317 AC: 265 AN: 835213

Other (OTH) AF: 0.000109 AC: 5 AN: 45869

GnomAD4 genome AF: 0.000234 AC: 26 AN: 111040 Hom.: 0 Cov.: 22 AF XY: 0.000301 AC XY: 10 AN XY: 33270

African (AFR) AF: 0.0000327 AC: 1 AN: 30544

American (AMR) AF: 0.000480 AC: 5 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000359 AC: 19 AN: 52976

Other (OTH) AF: 0.000670 AC: 1 AN: 1493

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.000230

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.78
MPC		1.3
ClinPred		0.088	T
GERP RS		3.9
PromoterAI		-0.022	Neutral
Varity_R		0.30
gMVP		0.86
Mutation Taster		=99/1	polymorphism

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: rs145115086; hg19: chrX-135730439; COSMIC: COSV65698277;