rs1957949

Variant names:

• chr14-65075889-C-T
• rs1957949
• ENST00000394606.6:n.*843G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000394606.6(MAX):​n.*843G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,066,874 control chromosomes in the GnomAD database, including 110,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23346 hom., cov: 33)
  • Exomes 𝑓: 0.43 (87126 hom.)
• Consequence: MAX ENST00000394606.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0550
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-65075889-C-T is Benign according to our data. Variant chr14-65075889-C-T is described in ClinVar as Benign. ClinVar VariationId is 313801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.*587G>A		3_prime_UTR_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.*587G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78714 AN: 151668 Hom.: 23289 Cov.: 33

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.468

GnomAD4 exome AF: 0.431 AC: 394490 AN: 915086 Hom.: 87126 Cov.: 30 AF XY: 0.430 AC XY: 181834 AN XY: 422524

African (AFR) AF: 0.858 AC: 16867 AN: 19650

American (AMR) AF: 0.295 AC: 1146 AN: 3888

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 3914 AN: 10250

East Asian (EAS) AF: 0.493 AC: 7399 AN: 15008

South Asian (SAS) AF: 0.491 AC: 8506 AN: 17322

European-Finnish (FIN) AF: 0.431 AC: 182 AN: 422

Middle Eastern (MID) AF: 0.378 AC: 798 AN: 2112

European-Non Finnish (NFE) AF: 0.419 AC: 340282 AN: 812360

Other (OTH) AF: 0.452 AC: 15396 AN: 34074

GnomAD4 genome AF: 0.519 AC: 78824 AN: 151788 Hom.: 23346 Cov.: 33 AF XY: 0.515 AC XY: 38203 AN XY: 74158

African (AFR) AF: 0.831 AC: 34376 AN: 41356

American (AMR) AF: 0.345 AC: 5260 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1341 AN: 3468

East Asian (EAS) AF: 0.418 AC: 2149 AN: 5144

South Asian (SAS) AF: 0.506 AC: 2439 AN: 4822

European-Finnish (FIN) AF: 0.428 AC: 4490 AN: 10488

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27313 AN: 67934

Other (OTH) AF: 0.468 AC: 987 AN: 2110

Alfa AF: 0.441 Hom.: 6350

Bravo AF: 0.523

Asia WGS AF: 0.482 AC: 1678 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.5
DANN	Benign	0.65
PhyloP100		0.055
Mutation Taster		=100/0	polymorphism (auto)

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: rs1957949; hg19: chr14-65542607; COSMIC: COSV52420205; COSMIC: COSV52420205;