Genetic Variant DCAF8:p.Arg317Ser (chr1-160237145-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_015726.4(DCAF8):c.949C>A(p.Arg317Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,176 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R317C) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DCAF8
NM_015726.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.41

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

giant axonal neuropathy 2
Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

DCAF8 links:

ENSG00000258465 (HGNC:):

ENSG00000258465 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-160237145-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133348.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.34197143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF8	NM_015726.4 link	c.949C>A	p.Arg317Ser	missense_variant	Exon 6 of 14	ENST00000368074.6	NP_056541.2	Q5TAQ9-1B7Z8C9
DCAF8	NR_028103.2 link	n.1482C>A		non_coding_transcript_exon_variant	Exon 6 of 14
DCAF8	NR_028104.2 link	n.1408C>A		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF8	ENST00000368074.6 link	c.949C>A	p.Arg317Ser	missense_variant	Exon 6 of 14	5	NM_015726.4	ENSP00000357053.1		Q5TAQ9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1413980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698594

African (AFR)

AF:

0.00

AC:

AN:

32818

American (AMR)

AF:

0.00

AC:

AN:

37740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25382

East Asian (EAS)

AF:

0.00

AC:

AN:

38306

South Asian (SAS)

AF:

0.00

AC:

AN:

80412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084754

Other (OTH)

AF:

0.00

AC:

AN:

58564

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

T;T;T;.

Eigen

Benign

0.011

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

.;.;T;.

M_CAP

Benign

0.082

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.34

N;N;N;.

PhyloP100

4.4

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.058

T;T;T;T

Sift4G

Uncertain

0.021

D;D;D;T

Polyphen

0.11

B;B;B;.

Vest4

0.67

MutPred

0.39

.;.;.;Gain of ubiquitination at K475 (P = 0.0281);

MVP

0.56

MPC

1.0

ClinPred

0.79

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.64

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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