rs1060500101

chr14-65077986-CATATACTGGAT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_002382.5(MAX):c.211_221del(p.Ile71AlafsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I71I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAX NM_002382.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PP5: Variant 14-65077986-CATATACTGGAT-C is Pathogenic according to our data. Variant chr14-65077986-CATATACTGGAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 404110.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAX	NM_002382.5	c.211_221del	p.Ile71AlafsTer12	frameshift_variant	4/5	ENST00000358664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAX	ENST00000358664.9	c.211_221del	p.Ile71AlafsTer12	frameshift_variant	4/5	1	NM_002382.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 03, 2016

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). This sequence change deletes 11 nucleotides from exon 4 of the MAX mRNA (c.211_221delATCCAGTATAT), causing a frameshift at codon 71. This creates a premature translational stop signal (p.Ile71Alafs*12) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060500101; hg19: chr14-65544704;