6-33322625-G-T

Variant names:

• chr6-33322625-G-T
• rs3130018
• NM_001141969.2:c.-53+237C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000374542.10(DAXX):​c.-53+237C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 155,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 28)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: DAXX ENST00000374542.10 intron
• Scores: Splicing: ADA: 0.00004088
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 publications found

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]

ENSG00000285064 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374542.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAXX	NM_001141969.2	MANE Select	c.-53+237C>A		intron	N/A	NP_001135441.1
	DAXX	NM_001141970.2		c.53+237C>A		intron	N/A	NP_001135442.1
	DAXX	NM_001350.5		c.-50+237C>A		intron	N/A	NP_001341.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAXX	ENST00000374542.10	TSL:1 MANE Select	c.-53+237C>A		intron	N/A	ENSP00000363668.5
	DAXX	ENST00000266000.10	TSL:1	c.-50+237C>A		intron	N/A	ENSP00000266000.6
	ENSG00000285064	ENST00000453407.7	TSL:5	n.*100-648C>A		intron	N/A	ENSP00000408499.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000644 AC: 1 AN: 155166 Hom.: 0 Cov.: 0 AF XY: 0.0000118 AC XY: 1 AN XY: 84496

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 3328

American (AMR) AF: 0.00 AC: 0 AN: 5006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4282

East Asian (EAS) AF: 0.00 AC: 0 AN: 8052

South Asian (SAS) AF: 0.00 AC: 0 AN: 31656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 600

European-Non Finnish (NFE) AF: 0.0000115 AC: 1 AN: 86744

Other (OTH) AF: 0.00 AC: 0 AN: 8386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		-1.3
PromoterAI		0.075	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3130018; hg19: chr6-33290402;