Genetic Variant DAXX:c.-53+237C>A (chr6-33322625-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001141969.2(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
NM_001141969.2 intron

Scores

Splicing: ADA: 0.00004088

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.25

Publications

0 publications found

Variant links:

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]

DAXX links:

ENSG00000285064 (HGNC:):

ENSG00000285064 links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAXX	NM_001141969.2 link	c.-53+237C>A		intron_variant	Intron 1 of 7	ENST00000374542.10	NP_001135441.1	Q9UER7-1A0A024RCS3Q53F85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAXX	ENST00000374542.10 link	c.-53+237C>A		intron_variant	Intron 1 of 7	1	NM_001141969.2	ENSP00000363668.5		Q9UER7-1
ENSG00000285064	ENST00000453407.7 link	n.*100-648C>A		intron_variant	Intron 2 of 3	5		ENSP00000408499.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000644

AC:

AN:

155166

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

84496

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

3328

American (AMR)

AF:

0.00

AC:

AN:

5006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4282

East Asian (EAS)

AF:

0.00

AC:

AN:

8052

South Asian (SAS)

AF:

0.00

AC:

AN:

31656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

600

European-Non Finnish (NFE)

AF:

0.0000115

AC:

AN:

86744

Other (OTH)

AF:

0.00

AC:

AN:

8386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.7

(source)

DANN

Benign

0.49

PhyloP100

-1.3

PromoterAI

0.075

Neutral

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over