chrX-136648355-T-G

Variant names:

• chrX-136648355-T-G
• rs104894774
• NM_000074.3:c.107T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000074.3(CD40LG):​c.107T>G​(p.Met36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M36K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.64
• Publications: 9 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: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136648355-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422070.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant X-136648355-T-G is Pathogenic according to our data. Variant chrX-136648355-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	NM_000074.3	MANE Select	c.107T>G	p.Met36Arg	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.107T>G	p.Met36Arg	missense	Exon 1 of 5	ENSP00000359663.2	P29965
	CD40LG	ENST00000370628.2	TSL:1	c.107T>G	p.Met36Arg	missense	Exon 1 of 4	ENSP00000359662.2	Q3L8U2
	CD40LG	ENST00000695724.1		c.107T>G	p.Met36Arg	missense	Exon 1 of 4	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000653 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hyper-IgM syndrome type 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.86		Gain of catalytic residue at M36 (P = 0.0101)
MVP		1.0
MPC		1.5
ClinPred		0.82	D
GERP RS		4.5
PromoterAI		0.020	Neutral
Varity_R		0.85
gMVP		0.92
Mutation Taster		=6/94	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: rs104894774; hg19: chrX-135730514;