chr8-127738434-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM5PP2PP3BP4_Strong

The NM_002467.6(MYC):c.217A>C(p.Thr73Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYC
NM_002467.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.08

Publications

42 publications found

Variant links:

Genes affected

MYC (HGNC:7553): (MYC proto-oncogene, bHLH transcription factor) This gene is a proto-oncogene and encodes a nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation. The encoded protein forms a heterodimer with the related transcription factor MAX. This complex binds to the E box DNA consensus sequence and regulates the transcription of specific target genes. Amplification of this gene is frequently observed in numerous human cancers. Translocations involving this gene are associated with Burkitt lymphoma and multiple myeloma in human patients. There is evidence to show that translation initiates both from an upstream, in-frame non-AUG (CUG) and a downstream AUG start site, resulting in the production of two isoforms with distinct N-termini. [provided by RefSeq, Aug 2017]

MYC links:

CASC11 (HGNC:48939): (cancer susceptibility 11)

CASC11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-127738434-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2658815.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2227 (below the threshold of 3.09). Trascript score misZ: 1.518 (below the threshold of 3.09). GenCC associations: The gene is linked to Burkitt lymphoma.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.014192492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYC	NM_002467.6 link	c.217A>C	p.Thr73Pro	missense_variant	Exon 2 of 3	ENST00000621592.8	NP_002458.2
MYC	NM_001354870.1 link	c.214A>C	p.Thr72Pro	missense_variant	Exon 2 of 3		NP_001341799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYC	ENST00000621592.8 link	c.217A>C	p.Thr73Pro	missense_variant	Exon 2 of 3	1	NM_002467.6	ENSP00000478887.2

Frequencies

GnomAD3 genomes

AF:

0.000219

AC:

AN:

150740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000400

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0114

AC:

2500

AN:

219638

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.000796

Gnomad ASJ exome

AF:

0.00746

Gnomad EAS exome

AF:

0.00285

Gnomad FIN exome

AF:

0.00913

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.00969

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00141

AC:

2031

AN:

1435484

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1139

AN XY:

712016

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000303

AC:

AN:

32966

American (AMR)

AF:

0.00101

AC:

AN:

42460

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

24914

East Asian (EAS)

AF:

0.000804

AC:

AN:

38572

South Asian (SAS)

AF:

0.000287

AC:

AN:

83488

European-Finnish (FIN)

AF:

0.00238

AC:

121

AN:

50796

Middle Eastern (MID)

AF:

0.00160

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00148

AC:

1621

AN:

1097240

Other (OTH)

AF:

0.00192

AC:

114

AN:

59422

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000219

AC:

AN:

150740

Hom.:

Cov.:

AF XY:

0.000299

AC XY:

AN XY:

73572

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000488

AC:

AN:

40988

American (AMR)

AF:

0.000198

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5066

South Asian (SAS)

AF:

0.00

AC:

AN:

4728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.000400

AC:

AN:

67520

Other (OTH)

AF:

0.00

AC:

AN:

2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000251

Hom.:

ExAC

AF:

0.0116

AC:

1409

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;T;D;D;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.091

T;T;T;T;T;T

MetaRNN

Benign

0.014

T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.0

.;.;.;M;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.6

D;D;.;.;D;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.029

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Vest4

0.39

ClinPred

0.043

GERP RS

4.8

Varity_R

0.83

gMVP

0.68

Mutation Taster

=6/94

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over