Genetic Variant MAX:n.*661G>A (chr14-65076071-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.91

Publications

2 publications found

Variant links:

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

MAX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MAX	NM_002382.5	MANE Select	c.*405G>A	3_prime_UTR	Exon 5 of 5	NP_002373.3
MAX	NR_073137.2		n.1012G>A	non_coding_transcript_exon	Exon 4 of 4
MAX	NR_176275.1		n.1131G>A	non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MAX	ENST00000394606.6	TSL:1	n.*661G>A	non_coding_transcript_exon	Exon 6 of 6	ENSP00000378104.2
MAX	ENST00000358664.9	TSL:1 MANE Select	c.*405G>A	3_prime_UTR	Exon 5 of 5	ENSP00000351490.4
MAX	ENST00000358402.8	TSL:1	c.*405G>A	3_prime_UTR	Exon 4 of 4	ENSP00000351175.4

Frequencies

GnomAD3 genomes

AF:

0.00805

AC:

1224

AN:

152130

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0115

AC XY:

5813

AN XY:

504986

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

23914

American (AMR)

AF:

0.00424

AC:

AN:

9204

Ashkenazi Jewish (ASJ)

AF:

0.000639

AC:

AN:

14082

East Asian (EAS)

AF:

0.00

AC:

AN:

21646

South Asian (SAS)

AF:

0.00570

AC:

214

AN:

37562

European-Finnish (FIN)

AF:

0.00929

AC:

AN:

9360

Middle Eastern (MID)

AF:

0.00595

AC:

AN:

2690

European-Non Finnish (NFE)

AF:

0.0128

AC:

11589

AN:

907990

Other (OTH)

AF:

0.0100

AC:

422

AN:

42174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

630

1261

1891

2522

3152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00803

AC:

1223

AN:

152246

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41546

American (AMR)

AF:

0.00562

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00539

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0108

AC:

114

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0130

AC:

884

AN:

68008

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00870

Hom.:

Bravo

AF:

0.00746

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

(source)

DANN

Benign

0.69

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over