1-160217707-C-T

Position:

chr1-160217707-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_015726.4(DCAF8):c.1679G>A(p.Arg560His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DCAF8
NM_015726.4 missense, splice_region

Scores

Splicing: ADA: 0.2426

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.63

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 -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.14264542).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCAF8	NM_015726.4 linkuse as main transcript	c.1679G>A	p.Arg560His	missense_variant, splice_region_variant	14/14	ENST00000368074.6	NP_056541.2	Q5TAQ9-1B7Z8C9
DCAF8	NR_028103.2 linkuse as main transcript	n.2212G>A		splice_region_variant, non_coding_transcript_exon_variant	14/14
DCAF8	NR_028104.2 linkuse as main transcript	n.2138G>A		splice_region_variant, non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCAF8	ENST00000368074.6 linkuse as main transcript	c.1679G>A	p.Arg560His	missense_variant, splice_region_variant	14/14	5	NM_015726.4	ENSP00000357053.1		Q5TAQ9-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249522

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135012

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460914

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726772

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Oct 19, 2023

The variant DCAF8:c.1679G>A, p.(Arg560His), which is located in the coding exon 14 of the DCAF8 gene, results from a guanine to adenine substitution at nucleotide position c.1679. The arginine at the protein position 560 is replaced by a histidine. This amino acid position is not located in a known functional domain of the protein. However, the DCAF8 gene shows an overall intolerance to missense changes (Z-score = 3.15). The variant is classified as rare in the overall population (allele frequency= 0.000008679 in gnomAD v4.1.0). In addition, in silico tools predict that this variant is tolerable (REVEL = 0.099). In summary, this variant is classified as a variant of unclear significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

T;T;T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

.;.;T;.

M_CAP

Benign

0.010

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

L;L;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.099

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.13

MutPred

0.31

.;.;.;Loss of MoRF binding (P = 0.0399);

MVP

0.30

MPC

1.1

ClinPred

0.59

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.099

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.36

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