rs387906649

Positions:

• chr14-65102339-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002382.5(MAX):​c.1A>G​(p.Met1?) variant causes a start lost 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_002382.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 5.52

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]

MAX (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-65102339-T-C is Pathogenic according to our data. Variant chr14-65102339-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 29785.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-65102339-T-C is described in Lovd as [Likely_pathogenic]. Variant chr14-65102339-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAX	NM_002382.5	c.1A>G	p.Met1?	start_lost	1/5	ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.1A>G	p.Met1?	start_lost	1/5	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Academic Department of Medical Genetics, University of Cambridge

Jan 26, 2018

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Pheochromocytoma, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 19, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;.;.;.;.;T;.;T;.;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PROVEAN	Uncertain	-3.5	D;D;.;N;D;D;N;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;.;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.85, 0.95, 0.99, 0.98	.;D;P;P;.;D;.;P;D;.;.;.
Vest4		0.84
MutPred		0.59		Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);Loss of phosphorylation at S2 (P = 0.5584);
MVP		0.99
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs387906649; hg19: chr14-65569057;