NM_000074.3:c.418T>C

Variant names:

• chrX-136659047-T-C
• rs104894777
• NM_000074.3:c.418T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000074.3(CD40LG):​c.418T>C​(p.Trp140Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W140C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.50
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136659049-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2138729.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant X-136659047-T-C is Pathogenic according to our data. Variant chrX-136659047-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 976233.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	NM_000074.3	MANE Select	c.418T>C	p.Trp140Arg	missense	Exon 5 of 5	NP_000065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.418T>C	p.Trp140Arg	missense	Exon 5 of 5	ENSP00000359663.2
	CD40LG	ENST00000370628.2	TSL:1	c.355T>C	p.Trp119Arg	missense	Exon 4 of 4	ENSP00000359662.2
	CD40LG	ENST00000695725.1		c.165T>C	p.Ser55Ser	synonymous	Exon 2 of 2	ENSP00000512123.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 1 Pathogenic:1

Jan 01, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.77		Loss of catalytic residue at L138 (P = 0.0028)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		1.0
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs104894777; hg19: chrX-135741206;