rs4645946

Positions:

• chr8-127736139-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001354870.1(MYC):​c.-455G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 432,244 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.018 (53 hom.)
• Consequence: MYC NM_001354870.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249

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]

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004051447).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0228 (3467/152330) while in subpopulation AFR AF= 0.039 (1623/41564). AF 95% confidence interval is 0.0375. There are 54 homozygotes in gnomad4. There are 1667 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3467 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYC	NM_001354870.1	c.-455G>A		5_prime_UTR_variant	1/3		NP_001341799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYC	ENST00000377970	c.-500G>A		5_prime_UTR_variant	1/3	1		ENSP00000367207.3
MYC	ENST00000259523	c.-500G>A		5_prime_UTR_variant	1/3	1		ENSP00000259523.6
MYC	ENST00000517291.2	c.-153-302G>A		intron_variant		1		ENSP00000429441.2

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3468 AN: 152212 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.0176 AC: 4914 AN: 279914 Hom.: 53 Cov.: 0 AF XY: 0.0176 AC XY: 2513 AN XY: 142512

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.0000801

Gnomad4 SAS exome AF: 0.0246

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0228 AC: 3467 AN: 152330 Hom.: 54 Cov.: 32 AF XY: 0.0224 AC XY: 1667 AN XY: 74484

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0196 Hom.: 49

Bravo AF: 0.0241

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0241 AC: 93

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.97
FATHMM_MKL	Benign	0.043	N
MetaRNN	Benign	0.0041	T
GERP RS		-0.29

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

Other links and lift over

dbSNP: rs4645946; hg19: chr8-128748385;