rs1059231

Positions:

• chr6-33320494-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001141969.2(DAXX):​c.1137T>C​(p.Tyr379=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,612,622 control chromosomes in the GnomAD database, including 71,056 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 0.24 (5352 hom., cov: 32)
  • Exomes 𝑓: 0.29 (65704 hom.)
• Consequence: DAXX NM_001141969.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226

Genes affected

DAXX (HGNC:2681): (death domain associated protein) This gene encodes a multifunctional protein that resides in multiple locations in the nucleus and in the cytoplasm. It interacts with a wide variety of proteins, such as apoptosis antigen Fas, centromere protein C, and transcription factor erythroblastosis virus E26 oncogene homolog 1. In the nucleus, the encoded protein functions as a potent transcription repressor that binds to sumoylated transcription factors. Its repression can be relieved by the sequestration of this protein into promyelocytic leukemia nuclear bodies or nucleoli. This protein also associates with centromeres in G2 phase. In the cytoplasm, the encoded protein may function to regulate apoptosis. The subcellular localization and function of this protein are modulated by post-translational modifications, including sumoylation, phosphorylation and polyubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP7: Synonymous conserved (PhyloP=-0.226 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAXX	NM_001141969.2	c.1137T>C	p.Tyr379=	synonymous_variant	4/8	ENST00000374542.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAXX	ENST00000374542.10	c.1137T>C	p.Tyr379=	synonymous_variant	4/8	1	NM_001141969.2	P2

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35890 AN: 151966 Hom.: 5359 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.203

GnomAD3 exomes AF: 0.298 AC: 74877 AN: 251304 Hom.: 12090 AF XY: 0.303 AC XY: 41091 AN XY: 135828

Gnomad AFR exome AF: 0.0515

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.252

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.295 AC: 430328 AN: 1460538 Hom.: 65704 Cov.: 33 AF XY: 0.296 AC XY: 215456 AN XY: 726704

Gnomad4 AFR exome AF: 0.0444

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.236 AC: 35887 AN: 152084 Hom.: 5352 Cov.: 32 AF XY: 0.242 AC XY: 17974 AN XY: 74334

Gnomad4 AFR AF: 0.0547

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.201

Alfa AF: 0.283 Hom.: 5275

Bravo AF: 0.219

Asia WGS AF: 0.233 AC: 811 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.3
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1059231; hg19: chr6-33288271; COSMIC: COSV56466529; COSMIC: COSV56466529;