chrX-136648286-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000074.3(CD40LG):c.38C>T(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,198,572 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 0 hom. 57 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.67

Publications

1 publications found

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 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

CD40LG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02560091).

BP6

Variant X-136648286-C-T is Benign according to our data. Variant chrX-136648286-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287380.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000108 (12/111372) while in subpopulation NFE AF = 0.000189 (10/53042). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 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.38C>T	p.Ala13Val	missense	Exon 1 of 5	NP_000065.1	P29965

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.38C>T	p.Ala13Val	missense	Exon 1 of 5	ENSP00000359663.2	P29965
CD40LG	ENST00000370628.2	TSL:1	c.38C>T	p.Ala13Val	missense	Exon 1 of 4	ENSP00000359662.2	Q3L8U2
CD40LG	ENST00000695724.1		c.38C>T	p.Ala13Val	missense	Exon 1 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111372

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000819

AC:

AN:

183233

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000147

AC:

160

AN:

1087200

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

353256

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26180

American (AMR)

AF:

0.00

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19324

East Asian (EAS)

AF:

0.00

AC:

AN:

30153

South Asian (SAS)

AF:

0.000111

AC:

AN:

53887

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.000181

AC:

151

AN:

832113

Other (OTH)

AF:

0.0000437

AC:

AN:

45742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000108

AC:

AN:

111372

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

33564

show subpopulations

African (AFR)

AF:

0.0000653

AC:

AN:

30639

American (AMR)

AF:

0.00

AC:

AN:

10475

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5949

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.000189

AC:

AN:

53042

Other (OTH)

AF:

0.00

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyper-IgM syndrome type 1 (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.4

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.71

M_CAP

Benign

0.013

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.8

PhyloP100

1.7

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.21

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.027

MVP

0.22

MPC

0.43

ClinPred

0.026

GERP RS

1.5

PromoterAI

-0.0027

Neutral

(source)

Varity_R

0.035

gMVP

0.70

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over