rs1395966308

Positions:

• chr14-65101552-T-A
• chr14-65101552-T-C
• chr14-65101552-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002382.5(MAX):​c.57A>T​(p.Gln19His) 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. 12/21 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q19L) 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: 2.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Protein max (size 158) in uniprot entity MAX_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_002382.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11761555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAX	NM_002382.5	c.57A>T	p.Gln19His	missense_variant	2/5	ENST00000358664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAX	ENST00000358664.9	c.57A>T	p.Gln19His	missense_variant	2/5	1	NM_002382.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.75	T;.;T;T;T;.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.050	N;N;N;N;.;N;N
MutationTaster	Benign	0.67	D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.070	N;.;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.55	T;.;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;.;B;.
Vest4		0.29
MutPred		0.20		Gain of catalytic residue at R17 (P = 0.0011);Gain of catalytic residue at R17 (P = 0.0011);Gain of catalytic residue at R17 (P = 0.0011);Gain of catalytic residue at R17 (P = 0.0011);Gain of catalytic residue at R17 (P = 0.0011);Gain of catalytic residue at R17 (P = 0.0011);Gain of catalytic residue at R17 (P = 0.0011);
MVP		0.68
MPC		0.93
ClinPred		0.22	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-65568270;