NM_001198956.2:c.269G>T

Variant names:

• chr1-167974846-G-T
• rs751118325
• NM_001198956.2:c.269G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS2_Supporting

The NM_001198956.2(DCAF6):​c.269G>T​(p.Arg90Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,537,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DCAF6 NM_001198956.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.24
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• BS2: High AC in GnomAd4 at 6 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.269G>T	p.Arg90Leu	missense	Exon 4 of 22	NP_001185885.1	Q58WW2-3
	DCAF6	NM_001349773.2		c.269G>T	p.Arg90Leu	missense	Exon 4 of 21	NP_001336702.1
	DCAF6	NM_001198957.2		c.176G>T	p.Arg59Leu	missense	Exon 3 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.269G>T	p.Arg90Leu	missense	Exon 4 of 22	ENSP00000356814.3	Q58WW2-3
	DCAF6	ENST00000312263.10	TSL:1	c.269G>T	p.Arg90Leu	missense	Exon 4 of 19	ENSP00000311949.6	Q58WW2-1
	DCAF6	ENST00000856062.1		c.269G>T	p.Arg90Leu	missense	Exon 4 of 22	ENSP00000526121.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000939 AC: 2 AN: 213022 AF XY: 0.00000863

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000196

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 40 AN: 1385814 Hom.: 0 Cov.: 30 AF XY: 0.0000306 AC XY: 21 AN XY: 685492

African (AFR) AF: 0.00 AC: 0 AN: 30890

American (AMR) AF: 0.00 AC: 0 AN: 34740

Ashkenazi Jewish (ASJ) AF: 0.0000417 AC: 1 AN: 24006

East Asian (EAS) AF: 0.00 AC: 0 AN: 37038

South Asian (SAS) AF: 0.0000286 AC: 2 AN: 69820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.0000326 AC: 35 AN: 1075066

Other (OTH) AF: 0.0000350 AC: 2 AN: 57160

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74258

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.010	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.84
Sift	Benign	0.039	D
Sift4G	Benign	0.26	T
Polyphen		0.81	P
Vest4		0.92
MutPred		0.56		Loss of MoRF binding (P = 0.0071)
MVP		0.87
MPC		1.3
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.47
gMVP		0.49
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs751118325; hg19: chr1-167944084;