rs11575983

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000074.3(CD40LG):ā€‹c.684A>Gā€‹(p.Val228Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,209,319 control chromosomes in the GnomAD database, including 22 homozygotes. There are 666 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.010 ( 14 hom., 326 hem., cov: 22)
Exomes š‘“: 0.0012 ( 8 hom. 340 hem. )

Consequence

CD40LG
NM_000074.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.591
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant X-136659313-A-G is Benign according to our data. Variant chrX-136659313-A-G is described in ClinVar as [Benign]. Clinvar id is 461469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.591 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1132/112050) while in subpopulation AFR AF= 0.0342 (1055/30827). AF 95% confidence interval is 0.0325. There are 14 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CD40LGNM_000074.3 linkuse as main transcriptc.684A>G p.Val228Val synonymous_variant 5/5 ENST00000370629.7 NP_000065.1 P29965

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CD40LGENST00000370629.7 linkuse as main transcriptc.684A>G p.Val228Val synonymous_variant 5/51 NM_000074.3 ENSP00000359663.2 P29965

Frequencies

GnomAD3 genomes
AF:
0.0101
AC:
1130
AN:
111998
Hom.:
14
Cov.:
22
AF XY:
0.00951
AC XY:
325
AN XY:
34164
show subpopulations
Gnomad AFR
AF:
0.0342
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00499
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000370
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000169
Gnomad OTH
AF:
0.00934
GnomAD3 exomes
AF:
0.00273
AC:
497
AN:
182002
Hom.:
5
AF XY:
0.00181
AC XY:
121
AN XY:
66672
show subpopulations
Gnomad AFR exome
AF:
0.0329
Gnomad AMR exome
AF:
0.00165
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000213
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000863
Gnomad OTH exome
AF:
0.00178
GnomAD4 exome
AF:
0.00119
AC:
1311
AN:
1097269
Hom.:
8
Cov.:
30
AF XY:
0.000938
AC XY:
340
AN XY:
362665
show subpopulations
Gnomad4 AFR exome
AF:
0.0379
Gnomad4 AMR exome
AF:
0.00242
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000741
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000796
Gnomad4 OTH exome
AF:
0.00326
GnomAD4 genome
AF:
0.0101
AC:
1132
AN:
112050
Hom.:
14
Cov.:
22
AF XY:
0.00952
AC XY:
326
AN XY:
34226
show subpopulations
Gnomad4 AFR
AF:
0.0342
Gnomad4 AMR
AF:
0.00499
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000371
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000169
Gnomad4 OTH
AF:
0.00922
Alfa
AF:
0.00437
Hom.:
19
Bravo
AF:
0.0122

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 21, 2018Variant summary: CD40LG c.684A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0035 in 198835 control chromosomes, predominantly at a frequency of 0.035 within the African subpopulation in the gnomAD database, including 8 homozygotes and 172 hemizygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 22-fold of the estimated maximal expected allele frequency for a pathogenic variant in CD40LG causing Hyper IgM Syndrome Type 1 phenotype (0.0016), while the overall frequency of the variant is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant; these data strongly suggest that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.684A>G in individuals affected with Hyper IgM Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Hyper-IgM syndrome type 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
CD40LG-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 13, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.63
CADD
Benign
3.2
DANN
Benign
0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11575983; hg19: chrX-135741472; API