chr8-127738434-A-C

Position:

chr8-127738434-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3PP5BP4

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. Variant has been reported in ClinVar as Likely pathogenic (no stars).

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

Likely pathogenic no assertion criteria provided P:5

Conservation

PhyloP100: 6.08

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue Phosphothreonine; by GSK3; alternate (size 0) in uniprot entity MYC_HUMAN

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]

PP5

Variant 8-127738434-A-C is Pathogenic according to our data. Variant chr8-127738434-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376458.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.014192492). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYC	NM_002467.6 linkuse as main transcript	c.217A>C	p.Thr73Pro	missense_variant	2/3	ENST00000621592.8	NP_002458.2
MYC	NM_001354870.1 linkuse as main transcript	c.214A>C	p.Thr72Pro	missense_variant	2/3		NP_001341799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYC	ENST00000621592.8 linkuse as main transcript	c.217A>C	p.Thr73Pro	missense_variant	2/3	1	NM_002467.6	ENSP00000478887	A2	P01106-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150740

Hom.:

Cov.:

FAILED QC

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

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

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.000804

Gnomad4 SAS exome

AF:

0.000287

Gnomad4 FIN exome

AF:

0.00238

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00192

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

Gnomad4 AFR

AF:

0.0000488

Gnomad4 AMR

AF:

0.000198

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000400

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

ExAC

AF:

0.0116

AC:

1409

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neuroblastoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Non-Hodgkin lymphoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

.;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

Pathogenic

3.2

.;.;.;M;.;.

MutationTaster

Benign

1.0

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

Polyphen

1.0

.;.;.;D;.;.

Vest4

0.39

ClinPred

0.043

GERP RS

4.8

Varity_R

0.83

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over