rs8064946

Variant names:

• chr17-7685993-G-C
• rs8064946
• NM_000546.6:c.-29+1384C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-7685993-G-C
• chr17-7685993-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000546.6(TP53):​c.-29+1384C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,228 control chromosomes in the GnomAD database, including 13,621 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 0.32 (13621 hom., cov: 33)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.830
• Publications: 27 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

WRAP53 (HGNC:25522): (WD repeat containing antisense to TP53) This gene encodes an essential component of the telomerase holoenzyme complex, a ribonucleoprotein complex required for telomere synthesis. This protein is enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. It interacts with dyskerin, TERT and TERC, other components of active telomerase, and with small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. This mRNA also functions as a p53 antisense transcript, that regulates endogenous p53 mRNA levels and further induction of p53 protein by targeting the 5' untranslated region of p53 mRNA. Alternatively spliced transcript variants which differ only in the 5' UTR have been found for this gene. [provided by RefSeq, Mar 2011]

WRAP53 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. 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
	TP53	NM_000546.6	MANE Select	c.-29+1384C>G		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.-26+1384C>G		intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.-132+1384C>G		intron	N/A	NP_001394191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.-29+1384C>G		intron	N/A	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.-26+1384C>G		intron	N/A	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.-263+1384C>G		intron	N/A	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47862 AN: 152094 Hom.: 13578 Cov.: 33

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.0625 AC: 1 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.0714 AC XY: 1 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.100 AC: 1 AN: 10

GnomAD4 genome AF: 0.315 AC: 47968 AN: 152212 Hom.: 13621 Cov.: 33 AF XY: 0.309 AC XY: 23033 AN XY: 74430

African (AFR) AF: 0.759 AC: 31511 AN: 41510

American (AMR) AF: 0.229 AC: 3498 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3470

East Asian (EAS) AF: 0.326 AC: 1688 AN: 5174

South Asian (SAS) AF: 0.286 AC: 1379 AN: 4828

European-Finnish (FIN) AF: 0.0618 AC: 656 AN: 10620

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8111 AN: 68018

Other (OTH) AF: 0.268 AC: 567 AN: 2114

Alfa AF: 0.0952 Hom.: 230

Bravo AF: 0.345

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.53
PhyloP100		-0.83
PromoterAI		-0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs8064946; hg19: chr17-7589311;