14-65076071-C-T

Variant names:

• chr14-65076071-C-T
• rs45440292
• ENST00000394606.6:n.*661G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000394606.6(MAX):​n.*661G>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 0.0112 in 1,220,868 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (6 hom., cov: 33)
  • Exomes 𝑓: 0.012 (77 hom.)
• Consequence: MAX ENST00000394606.6 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.91
• Publications: 2 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=-0.9).
• BP6: Variant 14-65076071-C-T is Benign according to our data. Variant chr14-65076071-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 313806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00803 (1223/152246) while in subpopulation NFE AF = 0.013 (884/68008). AF 95% confidence interval is 0.0123. There are 6 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1223 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAX	NM_002382.5	c.*405G>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.*405G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_002382.5	ENSP00000351490.4

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1224 AN: 152130 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.0116 AC: 12429 AN: 1068622 Hom.: 77 Cov.: 34 AF XY: 0.0115 AC XY: 5813 AN XY: 504986

African (AFR) AF: 0.00222 AC: 53 AN: 23914

American (AMR) AF: 0.00424 AC: 39 AN: 9204

Ashkenazi Jewish (ASJ) AF: 0.000639 AC: 9 AN: 14082

East Asian (EAS) AF: 0.00 AC: 0 AN: 21646

South Asian (SAS) AF: 0.00570 AC: 214 AN: 37562

European-Finnish (FIN) AF: 0.00929 AC: 87 AN: 9360

Middle Eastern (MID) AF: 0.00595 AC: 16 AN: 2690

European-Non Finnish (NFE) AF: 0.0128 AC: 11589 AN: 907990

Other (OTH) AF: 0.0100 AC: 422 AN: 42174

GnomAD4 genome AF: 0.00803 AC: 1223 AN: 152246 Hom.: 6 Cov.: 33 AF XY: 0.00768 AC XY: 572 AN XY: 74460

African (AFR) AF: 0.00207 AC: 86 AN: 41546

American (AMR) AF: 0.00562 AC: 86 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4828

European-Finnish (FIN) AF: 0.0108 AC: 114 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0130 AC: 884 AN: 68008

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00870 Hom.: 1

Bravo AF: 0.00746

ClinVar

Significance: Likely 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.90
CADD	Benign	1.8
DANN	Benign	0.69
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs45440292; hg19: chr14-65542789;