chr6-33320019-G-C

Position:

• chr6-33320019-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001141969.2(DAXX):​c.1457C>G​(p.Ala486Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 1,613,814 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (93 hom.)
• Consequence: DAXX NM_001141969.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.387

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019952655).
• BP6: Variant 6-33320019-G-C is Benign according to our data. Variant chr6-33320019-G-C is described in ClinVar as [Benign]. Clinvar id is 715804.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00606 (923/152268) while in subpopulation SAS AF= 0.0195 (94/4822). AF 95% confidence interval is 0.0163. There are 4 homozygotes in gnomad4. There are 415 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 923 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAXX	NM_001141969.2	c.1457C>G	p.Ala486Gly	missense_variant	5/8	ENST00000374542.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAXX	ENST00000374542.10	c.1457C>G	p.Ala486Gly	missense_variant	5/8	1	NM_001141969.2	P2

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152150 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00879 AC: 2181 AN: 248162 Hom.: 28 AF XY: 0.00955 AC XY: 1283 AN XY: 134360

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.00556

Gnomad SAS exome AF: 0.0202

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00896

Gnomad OTH exome AF: 0.00803

GnomAD4 exome AF: 0.00865 AC: 12641 AN: 1461546 Hom.: 93 Cov.: 33 AF XY: 0.00910 AC XY: 6614 AN XY: 727048

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.00277

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00847

Gnomad4 OTH exome AF: 0.00792

GnomAD4 genome AF: 0.00606 AC: 923 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00557 AC XY: 415 AN XY: 74452

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00853

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00722 Hom.: 3

Bravo AF: 0.00589

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00919 AC: 1116

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.63
DEOGEN2	Benign	0.23	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.060	N;N;N;.
REVEL	Benign	0.0070
Sift	Benign	0.12	T;T;T;.
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.033	B;B;.;.
Vest4		0.18
MVP		0.25
MPC		0.12
ClinPred		0.00039	T
GERP RS		-1.8
Varity_R		0.034
gMVP		0.028

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

Publications

LitVar

Other links and lift over

dbSNP: rs146304558; hg19: chr6-33287796; COSMIC: COSV56466706; COSMIC: COSV56466706;