14-65076599-G-T

Variant names:

• chr14-65076599-G-T
• rs1555340209
• NM_002382.5:c.360C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_002382.5(MAX):​c.360C>A​(p.Asn120Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MAX NM_002382.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.35

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a chain Protein max (size 158) in uniprot entity MAX_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_002382.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.1995976).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.360C>A	p.Asn120Lys	missense_variant	Exon 5 of 5	ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.360C>A	p.Asn120Lys	missense_variant	Exon 5 of 5	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Mar 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N120K variant (also known as c.360C>A), located in coding exon 5 of the MAX gene, results from a C to A substitution at nucleotide position 360. The asparagine at codon 120 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 120 of the MAX protein (p.Asn120Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAX-related conditions. ClinVar contains an entry for this variant (Variation ID: 463808). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.23	N;N;N;D
REVEL	Uncertain	0.30
Sift	Benign	0.091	T;T;T;D
Sift4G	Benign	0.92	T;T;T;D
Polyphen		0.0010	B;B;.;.
Vest4		0.26
MutPred		0.35		.;Gain of ubiquitination at N120 (P = 7e-04);.;.;
MVP		0.75
MPC		1.1
ClinPred		0.52	D
GERP RS		5.9
Varity_R		0.078
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555340209; hg19: chr14-65543317;