chr1-167974846-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BS2_Supporting

The NM_001198956.2(DCAF6):​c.269G>A​(p.Arg90His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,385,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R90L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: DCAF6 NM_001198956.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24

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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF6	NM_001198956.2	c.269G>A	p.Arg90His	missense_variant	Exon 4 of 22	ENST00000367840.4	NP_001185885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF6	ENST00000367840.4	c.269G>A	p.Arg90His	missense_variant	Exon 4 of 22	1	NM_001198956.2	ENSP00000356814.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000433 AC: 6 AN: 1385816 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 685492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	.;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.98	.;L;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.12	T;D;T;T
Sift4G	Benign	0.10	T;T;T;D
Polyphen		1.0, 0.98	.;D;D;D
Vest4		0.82
MutPred		0.52		.;Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);
MVP		0.70
MPC		1.3
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.34

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: rs751118325; hg19: chr1-167944084;