rs387906649

Variant names:

• chr14-65102339-T-C
• rs387906649
• NM_002382.5:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate 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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• polydactyly-macrocephaly syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 74 codons. Genomic position: 65077988. Lost 0.455 part of the original CDS.
• PS1: Another start lost variant in NM_002382.5 (MAX) was described as [Pathogenic] in ClinVar as 3707945
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.1A>G	p.Met1?	start_lost	Exon 1 of 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

Jan 26, 2018

Academic Department of Medical Genetics, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Jun 19, 2011

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		5.5
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
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.58
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906649; hg19: chr14-65569057;