chr14-65075759-A-G

Variant names:

• chr14-65075759-A-G
• rs4902358
• NM_002382.5:c.*717T>C

Variant summary

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

The NM_002382.5(MAX):​c.*717T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,065,706 control chromosomes in the GnomAD database, including 60,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6157 hom., cov: 32)
  • Exomes 𝑓: 0.34 (54343 hom.)
• Consequence: MAX NM_002382.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58
• 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: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.92).
• BP6: Variant 14-65075759-A-G is Benign according to our data. Variant chr14-65075759-A-G is described in ClinVar as Benign. ClinVar VariationId is 313798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002382.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAX	NM_002382.5	MANE Select	c.*717T>C		3_prime_UTR	Exon 5 of 5	NP_002373.3
	MAX	NM_001407094.1		c.*717T>C		3_prime_UTR	Exon 6 of 6	NP_001394023.1	P61244-1
	MAX	NM_001407095.1		c.*717T>C		3_prime_UTR	Exon 5 of 5	NP_001394024.1	P61244-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAX	ENST00000358664.9	TSL:1 MANE Select	c.*717T>C		3_prime_UTR	Exon 5 of 5	ENSP00000351490.4	P61244-1
	MAX	ENST00000358402.8	TSL:1	c.*717T>C		3_prime_UTR	Exon 4 of 4	ENSP00000351175.4	P61244-2
	MAX	ENST00000284165.10	TSL:1	c.*2044T>C		3_prime_UTR	Exon 4 of 4	ENSP00000284165.6	P61244-4

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41081 AN: 151906 Hom.: 6161 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.342 AC: 312501 AN: 913682 Hom.: 54343 Cov.: 33 AF XY: 0.343 AC XY: 144495 AN XY: 421856

African (AFR) AF: 0.149 AC: 2932 AN: 19632

American (AMR) AF: 0.180 AC: 622 AN: 3460

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 2243 AN: 10242

East Asian (EAS) AF: 0.212 AC: 3174 AN: 14972

South Asian (SAS) AF: 0.278 AC: 4775 AN: 17150

European-Finnish (FIN) AF: 0.365 AC: 250 AN: 684

Middle Eastern (MID) AF: 0.230 AC: 485 AN: 2108

European-Non Finnish (NFE) AF: 0.354 AC: 287430 AN: 811424

Other (OTH) AF: 0.311 AC: 10590 AN: 34010

GnomAD4 genome AF: 0.270 AC: 41082 AN: 152024 Hom.: 6157 Cov.: 32 AF XY: 0.271 AC XY: 20113 AN XY: 74312

African (AFR) AF: 0.166 AC: 6876 AN: 41490

American (AMR) AF: 0.211 AC: 3226 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3466

East Asian (EAS) AF: 0.144 AC: 745 AN: 5158

South Asian (SAS) AF: 0.280 AC: 1351 AN: 4824

European-Finnish (FIN) AF: 0.397 AC: 4192 AN: 10546

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23041 AN: 67954

Other (OTH) AF: 0.239 AC: 503 AN: 2108

Alfa AF: 0.302 Hom.: 9527

Bravo AF: 0.249

Asia WGS AF: 0.200 AC: 695 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	-0.92
CADD	Benign	0.22
DANN	Benign	0.47
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
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: rs4902358; hg19: chr14-65542477;