rs1680191601

Variant names:

• chr1-167987570-C-T
• rs1680191601
• NM_001198956.2:c.514C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001198956.2(DCAF6):​c.514C>T​(p.Arg172Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,602 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DCAF6 NM_001198956.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF6	NM_001198956.2	c.514C>T	p.Arg172Cys	missense_variant	Exon 5 of 22	ENST00000367840.4	NP_001185885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF6	ENST00000367840.4	c.514C>T	p.Arg172Cys	missense_variant	Exon 5 of 22	1	NM_001198956.2	ENSP00000356814.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450602 Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2 AN XY: 722316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514C>T (p.R172C) alteration is located in exon 5 (coding exon 5) of the DCAF6 gene. This alteration results from a C to T substitution at nucleotide position 514, causing the arginine (R) at amino acid position 172 to be replaced by a cysteine (C). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	.;.;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.6	.;H;H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.97
MutPred		0.57		.;Gain of methylation at K174 (P = 0.0582);Gain of methylation at K174 (P = 0.0582);Gain of methylation at K174 (P = 0.0582);
MVP		0.91
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1680191601; hg19: chr1-167956808; COSMIC: COSV105888813; COSMIC: COSV105888813;