8-127738294-A-G

Position:

chr8-127738294-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002467.6(MYC):c.77A>G(p.Asn26Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0319 in 1,610,196 control chromosomes in the GnomAD database, including 1,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.024 ( 72 hom., cov: 33)

Exomes 𝑓: 0.033 ( 940 hom. )

Consequence

MYC
NM_002467.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 5.19

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0082629025).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.024 (3648/152296) while in subpopulation NFE AF= 0.0363 (2466/68022). AF 95% confidence interval is 0.0351. There are 72 homozygotes in gnomad4. There are 1653 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 3648 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYC	NM_002467.6 linkuse as main transcript	c.77A>G	p.Asn26Ser	missense_variant	2/3	ENST00000621592.8
MYC	NM_001354870.1 linkuse as main transcript	c.74A>G	p.Asn25Ser	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYC	ENST00000621592.8 linkuse as main transcript	c.77A>G	p.Asn26Ser	missense_variant	2/3	1	NM_002467.6	A2	P01106-2

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3651

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0230

AC:

5750

AN:

249536

Hom.:

AF XY:

0.0231

AC XY:

3117

AN XY:

134904

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0427

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0344

Gnomad OTH exome

AF:

0.0289

GnomAD4 exome

AF:

0.0327

AC:

47736

AN:

1457900

Hom.:

940

Cov.:

AF XY:

0.0318

AC XY:

23053

AN XY:

724576

show subpopulations

Gnomad4 AFR exome

AF:

0.00683

Gnomad4 AMR exome

AF:

0.0207

Gnomad4 ASJ exome

AF:

0.0425

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00392

Gnomad4 FIN exome

AF:

0.0160

Gnomad4 NFE exome

AF:

0.0383

Gnomad4 OTH exome

AF:

0.0278

GnomAD4 genome

AF:

0.0240

AC:

3648

AN:

152296

Hom.:

Cov.:

AF XY:

0.0222

AC XY:

1653

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00705

Gnomad4 AMR

AF:

0.0282

Gnomad4 ASJ

AF:

0.0441

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0181

Gnomad4 NFE

AF:

0.0363

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0336

Hom.:

259

Bravo

AF:

0.0251

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0397

AC:

341

ExAC

AF:

0.0221

AC:

2686

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0380

EpiControl

AF:

0.0401

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic Hodgkin lymphoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pathology Department, Puerta del Mar University Hospital

Oct 01, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

MYC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;T;T;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

T;T;T;T;T;T

MetaRNN

Benign

0.0083

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;.;.;M;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;.;.;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.018

D;D;.;.;D;.

Sift4G

Benign

0.081

T;D;D;T;D;D

Polyphen

0.98

.;.;.;D;.;.

Vest4

0.14

ClinPred

0.035

GERP RS

3.9

Varity_R

0.42

gMVP

0.50

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