14-65093792-A-T

Variant names:

• chr14-65093792-A-T
• rs771488967
• NM_002382.5:c.87T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002382.5(MAX):​c.87T>A​(p.Asn29Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N29N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_002382.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64
• 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

ENSG00000259118 (HGNC:58293):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a domain bHLH (size 51) in uniprot entity MAX_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002382.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.87T>A	p.Asn29Lys	missense_variant	Exon 3 of 5	ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.87T>A	p.Asn29Lys	missense_variant	Exon 3 of 5	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;.;.;.;D;.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;M;M;M;M;.;.;.;M
PhyloP100		3.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D;D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;D;D;D;.;.;.
Vest4		0.80
MutPred		0.53		Loss of ubiquitination at K24 (P = 0.0116);.;Loss of ubiquitination at K24 (P = 0.0116);Loss of ubiquitination at K24 (P = 0.0116);Loss of ubiquitination at K24 (P = 0.0116);Loss of ubiquitination at K24 (P = 0.0116);.;.;.;Loss of ubiquitination at K24 (P = 0.0116);
MVP		0.95
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.98
Mutation Taster		=2/98	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: rs771488967; hg19: chr14-65560510;