9-34096720-G-A

Variant names:

• chr9-34096720-G-A
• rs774034512
• NM_015397.4:c.857C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015397.4(DCAF12):​c.857C>T​(p.Ser286Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,380 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCAF12 NM_015397.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• Publications: 0 publications found

Genes affected

DCAF12 (HGNC:19911): (DDB1 and CUL4 associated factor 12) This gene encodes a WD repeat-containing protein that interacts with the COP9 signalosome, a macromolecular complex that interacts with cullin-RING E3 ligases and regulates their activity by hydrolyzing cullin-Nedd8 conjugates. [provided by RefSeq, Jul 2009]

DCAF12-AS1 (HGNC:58097):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37543195).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015397.4. 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
	DCAF12	NM_015397.4	MANE Select	c.857C>T	p.Ser286Phe	missense	Exon 6 of 9	NP_056212.1	Q5T6F0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF12	ENST00000361264.9	TSL:1 MANE Select	c.857C>T	p.Ser286Phe	missense	Exon 6 of 9	ENSP00000355114.3	Q5T6F0
	DCAF12	ENST00000911965.1		c.857C>T	p.Ser286Phe	missense	Exon 6 of 9	ENSP00000582024.1
	DCAF12	ENST00000954259.1		c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	ENSP00000624318.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461380 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727046

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111636

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	Benign	0.13
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.017	D
Polyphen		0.98	D
Vest4		0.19
MutPred		0.49		Loss of disorder (P = 0.0204)
MVP		0.85
MPC		0.48
ClinPred		0.85	D
GERP RS		4.6
Varity_R		0.22
gMVP		0.35
Mutation Taster		=30/70	disease causing

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: rs774034512; hg19: chr9-34096718;