rs4645946

Variant names:

• chr8-127736139-G-A
• rs4645946
• ENST00000377970.6:c.-500G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354870.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYC	NM_001354870.1		c.-455G>A		5_prime_UTR	Exon 1 of 3	NP_001341799.1	P01106-3
	MYC	NM_002467.6	MANE Select	c.-455G>A		upstream_gene	N/A	NP_002458.2	P01106-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYC	ENST00000377970.6	TSL:1	c.-500G>A		5_prime_UTR	Exon 1 of 3	ENSP00000367207.3	P01106-1
	MYC	ENST00000259523.10	TSL:1	c.-500G>A		5_prime_UTR	Exon 1 of 3	ENSP00000259523.6	A0A0B4J1R1
	MYC	ENST00000517291.2	TSL:1	c.-153-302G>A		intron	N/A	ENSP00000429441.2	H0YBG3

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

African (AFR) AF: 0.0372 AC: 296 AN: 7954

American (AMR) AF: 0.0128 AC: 136 AN: 10662

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 175 AN: 9818

East Asian (EAS) AF: 0.0000801 AC: 2 AN: 24966

South Asian (SAS) AF: 0.0246 AC: 185 AN: 7520

European-Finnish (FIN) AF: 0.0185 AC: 407 AN: 22002

Middle Eastern (MID) AF: 0.0310 AC: 43 AN: 1388

European-Non Finnish (NFE) AF: 0.0187 AC: 3326 AN: 177690

Other (OTH) AF: 0.0192 AC: 344 AN: 17914

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

African (AFR) AF: 0.0390 AC: 1623 AN: 41564

American (AMR) AF: 0.0137 AC: 210 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4832

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1225 AN: 68032

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0196 Hom.: 73

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.97
FATHMM_MKL	Benign	0.043	N
MetaRNN	Benign	0.0041	T
PhyloP100		-0.25
GERP RS		-0.29
PromoterAI		0.037	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs4645946; hg19: chr8-128748385;