Genetic Variant DCAF8L1:p.Gly591Ala (chrX-27979563-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001017930.2(DCAF8L1):c.1772G>C(p.Gly591Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,206,924 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 3 hem. )

Consequence

DCAF8L1
NM_001017930.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

Publications

0 publications found

Variant links:

Genes affected

DCAF8L1 (HGNC:31810): (DDB1 and CUL4 associated factor 8 like 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by Gly-His and Trp-Asp (GH-WD), which may facilitate the formation of heterotrimeric or multi-protein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene appears to represent an intronless retrocopy of a related multi-exon gene located on chromosome 1. However, the CDS of this intronless gene remains intact, it is conserved in other primate species, it is known to be transcribed, and it is therefore thought to encode a functional protein. [provided by RefSeq, May 2010]

DCAF8L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042229205).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF8L1	NM_001017930.2 link	c.1772G>C	p.Gly591Ala	missense_variant	Exon 1 of 1	ENST00000441525.4	NP_001017930.1	A6NGE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF8L1	ENST00000441525.4 link	c.1772G>C	p.Gly591Ala	missense_variant	Exon 1 of 1	6	NM_001017930.2	ENSP00000405222.1		A6NGE4

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000337

AC:

AN:

178275

AF XY:

0.0000317

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000865

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1094936

Hom.:

Cov.:

AF XY:

0.00000832

AC XY:

AN XY:

360724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26378

American (AMR)

AF:

0.00

AC:

AN:

35051

Ashkenazi Jewish (ASJ)

AF:

0.000732

AC:

AN:

19127

East Asian (EAS)

AF:

0.00

AC:

AN:

30162

South Asian (SAS)

AF:

0.00

AC:

AN:

53488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840266

Other (OTH)

AF:

0.0000435

AC:

AN:

45950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30818

American (AMR)

AF:

0.00

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3535

South Asian (SAS)

AF:

0.00

AC:

AN:

2689

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53180

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1772G>C (p.G591A) alteration is located in exon 1 (coding exon 1) of the DCAF8L1 gene. This alteration results from a G to C substitution at nucleotide position 1772, causing the glycine (G) at amino acid position 591 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.53

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.023

FATHMM_MKL

Benign

0.084

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0027

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.8

PhyloP100

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

REVEL

Benign

0.085

Sift

Uncertain

0.0090

Sift4G

Benign

0.18

Polyphen

0.37

Vest4

0.085

MVP

0.24

MPC

0.13

ClinPred

0.083

GERP RS

-0.17

Varity_R

0.14

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(source)

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

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over