14-65076584-G-T

Variant names:

• chr14-65076584-G-T
• rs370238588
• NM_002382.5:c.375C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002382.5(MAX):​c.375C>A​(p.Asn125Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N125S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_002382.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002382.5. 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
	MAX	NM_002382.5	MANE Select	c.375C>A	p.Asn125Lys	missense	Exon 5 of 5	NP_002373.3
	MAX	NM_001407094.1		c.375C>A	p.Asn125Lys	missense	Exon 6 of 6	NP_001394023.1
	MAX	NM_001407095.1		c.348C>A	p.Asn116Lys	missense	Exon 5 of 5	NP_001394024.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAX	ENST00000358664.9	TSL:1 MANE Select	c.375C>A	p.Asn125Lys	missense	Exon 5 of 5	ENSP00000351490.4
	MAX	ENST00000358402.8	TSL:1	c.348C>A	p.Asn116Lys	missense	Exon 4 of 4	ENSP00000351175.4
	MAX	ENST00000394606.6	TSL:1	n.*148C>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000378104.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N125K variant (also known as c.375C>A), located in coding exon 5 of the MAX gene, results from a C to A substitution at nucleotide position 375. The asparagine at codon 125 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.47
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.98	D
Vest4		0.74
MutPred		0.34		Gain of ubiquitination at N125 (P = 0.0037)
MVP		0.88
MPC		1.2
ClinPred		0.73	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.64
Mutation Taster		=41/59	disease causing

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: rs370238588; hg19: chr14-65543302;