ENST00000394606.6:n.*821G>A

Variant names:

• chr14-65075911-C-T
• rs1957948
• ENST00000394606.6:n.*821G>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.*821G>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 0.413 in 1,066,772 control chromosomes in the GnomAD database, including 95,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20241 hom., cov: 32)
  • Exomes 𝑓: 0.40 (75747 hom.)
• Consequence: MAX ENST00000394606.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.115
• Publications: 18 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=-0.76).
• BP6: Variant 14-65075911-C-T is Benign according to our data. Variant chr14-65075911-C-T is described in ClinVar as Benign. ClinVar VariationId is 313802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394606.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAX	NM_002382.5	MANE Select	c.*565G>A		3_prime_UTR	Exon 5 of 5	NP_002373.3
	MAX	NR_073137.2		n.1172G>A		non_coding_transcript_exon	Exon 4 of 4
	MAX	NR_176275.1		n.1291G>A		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAX	ENST00000394606.6	TSL:1	n.*821G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000378104.2
	MAX	ENST00000358664.9	TSL:1 MANE Select	c.*565G>A		3_prime_UTR	Exon 5 of 5	ENSP00000351490.4
	MAX	ENST00000358402.8	TSL:1	c.*565G>A		3_prime_UTR	Exon 4 of 4	ENSP00000351175.4

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73140 AN: 151552 Hom.: 20197 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.401 AC: 366899 AN: 915102 Hom.: 75747 Cov.: 30 AF XY: 0.400 AC XY: 169111 AN XY: 422568

African (AFR) AF: 0.804 AC: 15798 AN: 19644

American (AMR) AF: 0.259 AC: 1026 AN: 3956

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 2994 AN: 10242

East Asian (EAS) AF: 0.491 AC: 7382 AN: 15022

South Asian (SAS) AF: 0.476 AC: 8287 AN: 17392

European-Finnish (FIN) AF: 0.416 AC: 174 AN: 418

Middle Eastern (MID) AF: 0.338 AC: 711 AN: 2104

European-Non Finnish (NFE) AF: 0.389 AC: 316291 AN: 812262

Other (OTH) AF: 0.418 AC: 14236 AN: 34062

GnomAD4 genome AF: 0.483 AC: 73232 AN: 151670 Hom.: 20241 Cov.: 32 AF XY: 0.480 AC XY: 35563 AN XY: 74080

African (AFR) AF: 0.774 AC: 31974 AN: 41312

American (AMR) AF: 0.308 AC: 4702 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1003 AN: 3460

East Asian (EAS) AF: 0.414 AC: 2131 AN: 5144

South Asian (SAS) AF: 0.495 AC: 2385 AN: 4820

European-Finnish (FIN) AF: 0.421 AC: 4396 AN: 10450

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25299 AN: 67910

Other (OTH) AF: 0.429 AC: 906 AN: 2110

Alfa AF: 0.398 Hom.: 6831

Bravo AF: 0.483

Asia WGS AF: 0.467 AC: 1624 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.5
DANN	Benign	0.84
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1957948; hg19: chr14-65542629; COSMIC: COSV52420215; COSMIC: COSV52420215;