chr1-168045209-G-A

Variant names:

• chr1-168045209-G-A
• rs145189179
• NM_001198956.2:c.2240G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS2_Supporting

The NM_001198956.2(DCAF6):​c.2240G>A​(p.Arg747Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000498 in 1,607,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: DCAF6 NM_001198956.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.20
• Publications: 4 publications found

Genes affected

DCAF6 (HGNC:30002): (DDB1 and CUL4 associated factor 6) The protein encoded by this gene is a ligand-dependent coactivator of nuclear receptors, including nuclear receptor subfamily 3 group C member 1 (NR3C1), glucocorticoid receptor (GR), and androgen receptor (AR). The encoded protein and DNA damage binding protein 2 (DDB2) may act as tumor promoters and tumor suppressors, respectively, by regulating the level of androgen receptor in prostate tissues. In addition, this protein can act with glucocorticoid receptor to promote human papillomavirus gene expression. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant 1-168045209-G-A is Pathogenic according to our data. Variant chr1-168045209-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224814.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14479268). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 57 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198956.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF6	NM_001198956.2	MANE Select	c.2240G>A	p.Arg747Gln	missense	Exon 16 of 22	NP_001185885.1	Q58WW2-3
	DCAF6	NM_001349773.2		c.2240G>A	p.Arg747Gln	missense	Exon 16 of 21	NP_001336702.1
	DCAF6	NM_001198957.2		c.2147G>A	p.Arg716Gln	missense	Exon 15 of 21	NP_001185886.1	Q58WW2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF6	ENST00000367840.4	TSL:1 MANE Select	c.2240G>A	p.Arg747Gln	missense	Exon 16 of 22	ENSP00000356814.3	Q58WW2-3
	DCAF6	ENST00000312263.10	TSL:1	c.2009G>A	p.Arg670Gln	missense	Exon 14 of 19	ENSP00000311949.6	Q58WW2-1
	DCAF6	ENST00000856062.1		c.2237G>A	p.Arg746Gln	missense	Exon 16 of 22	ENSP00000526121.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000720 AC: 176 AN: 244578 AF XY: 0.000763

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000209

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000959

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000510 AC: 743 AN: 1455566 Hom.: 0 Cov.: 31 AF XY: 0.000553 AC XY: 400 AN XY: 723534

African (AFR) AF: 0.0000604 AC: 2 AN: 33092

American (AMR) AF: 0.00106 AC: 46 AN: 43582

Ashkenazi Jewish (ASJ) AF: 0.000194 AC: 5 AN: 25718

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39624

South Asian (SAS) AF: 0.000764 AC: 65 AN: 85088

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53306

Middle Eastern (MID) AF: 0.00315 AC: 18 AN: 5712

European-Non Finnish (NFE) AF: 0.000482 AC: 535 AN: 1109366

Other (OTH) AF: 0.000832 AC: 50 AN: 60078

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74330

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.00118 AC: 18 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000733 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral visual impairment and intellectual disability (1)
-	1	-	DCAF6-related condition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.58
MPC		1.2
ClinPred		0.36	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.52
Mutation Taster		=90/10	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs145189179; hg19: chr1-168014447; COSMIC: COSV99044147;