14-65077907-G-C

Variant names:

• chr14-65077907-G-C
• rs146552320
• ENST00000284165.10:c.301C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000284165.10(MAX):​c.301C>G​(p.His101Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H101Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX ENST00000284165.10 missense
• Scores: Splicing: ADA: 0.0003552
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48
• 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 10 uncertain in ENST00000284165.10
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08632848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.295+6C>G		splice_region_variant, intron_variant	Intron 4 of 4	ENST00000358664.9	NP_002373.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAX	ENST00000358664.9	c.295+6C>G		splice_region_variant, intron_variant	Intron 4 of 4	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.087	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.23	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Uncertain	0.15	D
PhyloP100		3.5
PROVEAN	Benign	-0.37	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.28	T;T
Sift4G	Benign	0.43	T;T
Vest4		0.24
MutPred		0.28		Gain of catalytic residue at Q98 (P = 0.0107);.;
MVP		0.38
ClinPred		0.094	T
GERP RS		3.6
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.044
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: rs146552320; hg19: chr14-65544625;