Variant chr1-160237135-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_015726.4(DCAF8):c.959C>T(p.Ser320Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000705 in 1,559,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

DCAF8
NM_015726.4 missense, splice_region

Scores

Splicing: ADA: 0.9910

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19

Variant links:

Genes affected

DCAF8 (HGNC:24891): (DDB1 and CUL4 associated factor 8) This gene encodes a WD repeat-containing protein that interacts with the Cul4-Ddb1 E3 ligase macromolecular complex. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2009]

DCAF8 links:

DCAF8 (HGNC:):

DCAF8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DCAF8. . Gene score misZ 3.1538 (greater than the threshold 3.09). Trascript score misZ 4.3168 (greater than threshold 3.09). GenCC has associacion of gene with giant axonal neuropathy 2.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCAF8	NM_015726.4 linkuse as main transcript	c.959C>T	p.Ser320Leu	missense_variant, splice_region_variant	6/14	ENST00000368074.6	NP_056541.2	Q5TAQ9-1B7Z8C9
DCAF8	NR_028103.2 linkuse as main transcript	n.1492C>T		splice_region_variant, non_coding_transcript_exon_variant	6/14
DCAF8	NR_028104.2 linkuse as main transcript	n.1418C>T		splice_region_variant, non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCAF8	ENST00000368074.6 linkuse as main transcript	c.959C>T	p.Ser320Leu	missense_variant, splice_region_variant	6/14	5	NM_015726.4	ENSP00000357053.1		Q5TAQ9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000711

AC:

AN:

1407262

Hom.:

Cov.:

AF XY:

0.00000575

AC XY:

AN XY:

695078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000272

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000740

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DCAF8-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

The DCAF8 c.959C>T variant is predicted to result in the amino acid substitution p.Ser320Leu. This variant occurs at the terminal nucleotide of an exon and is predicted to have a minor impact on splicing at the consensus splice site (Alamut Visual Plus v.1.6.1). However, these prediction programs are not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0038% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-160206925-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T;T;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;.;D;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

M;M;M;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.98

D;D;D;.

Vest4

0.40

MutPred

0.34

.;.;.;Loss of disorder (P = 0.0292);

MVP

0.57

MPC

1.0

ClinPred

0.88

GERP RS

5.7

Varity_R

0.32

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over