rs786203385

chr14-65077912-C-Achr14-65077912-C-Gchr14-65077912-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_002382.5(MAX):c.295+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_002382.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.86

Genes affected

MAX (HGNC:6913): (MYC associated factor X) The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. Myc is an oncoprotein implicated in cell proliferation, differentiation and apoptosis. The homodimers and heterodimers compete for a common DNA target site (the E box) and rearrangement among these dimer forms provides a complex system of transcriptional regulation. Mutations of this gene have been reported to be associated with hereditary pheochromocytoma. A pseudogene of this gene is located on the long arm of chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.2, offset of 49, new splice context is: cagGTcagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 14-65077912-C-A is Pathogenic according to our data. Variant chr14-65077912-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1458939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAX	NM_002382.5	c.295+1G>T		splice_donor_variant		ENST00000358664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAX	ENST00000358664.9	c.295+1G>T		splice_donor_variant		1	NM_002382.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2021

The c.295+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the MAX gene. This alteration occurs at the 3' terminus of the MAX gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 103 amino acids of the protein. The exact functional effect of this alteration is unknown; however, and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in an individual affected with bilateral pheochromocytoma and a paraganglioma whose tumor demonstrated loss of heterozygosity and absence of MAX protein staining by immunohistochemistry (Burnichon N et al. Clin Cancer Res, 2012 May;18:2828-37). Another alteration impacting the same donor site (c.295+1G>A) has been identified in one individual with personal and family history of pheochromocytoma (PCC) in which the proband's PCC tumor demonstrated loss of heterozygosity as well as absent MAX staining via immunohistochemistry. In addition, RT-PCR analysis revealed that the c.295+1G>A allele was associated with complete skipping of exon 4 in tumor cDNA (Comino-Méndez I et al. Nat. Genet. 2011 Jul; 43(7):663-7). The c.295+1G>T variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminal domain of the MAX protein, which is essential for protein localization to the nucleus and suppression of MYC transactivation activity (PMID: 1459463, 1730412, 7630640). While functional studies have not been performed to directly test the effect of this variant on MAX protein function, this suggests that disruption of this region of the protein is causative of disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 4, which introduces a new termination codon (PMID: 21685915). However the mRNA is not expected to undergo nonsense-mediated decay. Disruption of this splice site has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 22452945, 21685915). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the MAX gene. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.32	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
ClinPred		0.86	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -48
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-65544630;