Variant X-136659171-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000074.3(CD40LG):c.542G>C(p.Arg181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000686 in 1,209,725 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 14 hem., cov: 22)

Exomes 𝑓: 0.000036 ( 0 hom. 5 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.340

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]

CD40LG links:

CD40LG (HGNC:):

CD40LG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a chain CD40 ligand, membrane form (size 260) in uniprot entity CD40L_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000074.3

BP4

Computational evidence support a benign effect (MetaRNN=0.041614532).

BP6

Variant X-136659171-G-C is Benign according to our data. Variant chrX-136659171-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439470.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000393 (44/111870) while in subpopulation AFR AF= 0.00137 (42/30760). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40LG	NM_000074.3 linkuse as main transcript	c.542G>C	p.Arg181Pro	missense_variant	5/5	ENST00000370629.7	NP_000065.1	P29965

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7 linkuse as main transcript	c.542G>C	p.Arg181Pro	missense_variant	5/5	1	NM_000074.3	ENSP00000359663.2		P29965

Frequencies

GnomAD3 genomes

AF:

0.000393

AC:

AN:

111870

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

AN XY:

34024

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000928

AC:

AN:

183179

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

67727

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000355

AC:

AN:

1097855

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363215

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.000393

AC:

AN:

111870

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

AN XY:

34024

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000442

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 24, 2017

- -

Hyper-IgM syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;T

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.042

T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.024

D;D

Sift4G

Benign

0.22

T;T

Polyphen

0.93

P;P

Vest4

0.065

MVP

0.68

MPC

0.73

ClinPred

0.028

GERP RS

1.9

Varity_R

0.74

gMVP

0.68

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over